Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors

ABSTRACT

The present invention provides methods for the treatment of obesity using sterol or 5α-stanol absorption inhibitors and compositions and therapeutic combinations including sterol or 5α-stanol absorption inhibitors and at least one obesity control medication.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority from U.S.Provisional Patent Application Serial No. 60/323,840, filed Sep. 21,2001, and is a continuation-in-part of U.S. patent application Ser. No.10/166,942, filed Jun. 11, 2002, each incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to compositions and therapeuticcombinations for treating obesity in a subject comprising theadministration of sterol and/or 5α-stanol absorption inhibitor(s) orcombinations with obesity control medications.

BACKGROUND OF THE INVENTION

[0003] Obesity is one of the most common medical problems in the UnitedStates and other developed countries and a risk factor for otherillnesses, such as hypertension, diabetes, degenerative arthritis andmyocardial infarction. Weight loss medications may be appropriate foruse in selected patients who are obese or who are overweight withco-morbid conditions.

[0004] One measure for defining obesity is known as a body mass index(BMI), which is weight in kilograms divided by height in meters squared.A BMI of 18.5 to 24.9 is generally classified as normal, a BMI of 25.0to 29.9 is generally classified as overweight and a BMI of 30 or greateris generally classified as obese. Alternatively, obesity may be definedas the top percentile, such as 15 percent, of a population's weight fora given height. Such definitions of obesity, however, are not a measureof body composition and different people may have higher or lower levelsof body fat or muscle mass for their height. Nevertheless, thesedefinitions of obesity are useful characterizations for generalpopulations of people.

[0005] The goal of obesity treatment is to exert a negative energybalance on the system by reducing energy input or increasing energyoutput, or both. Obesity is caused by a constellation of factorsincluding, but not limited to, excessive energy intake (food),insufficient energy output (exercise), low resting metabolic rate,genetic predisposition, low fat oxidation rate, low sympathetic activityand high plasma leptin level. These factors may also have severalcauses. For example, a low resting metabolic rate may be due to geneticvariation involving sympathetic activity, thyroid activity, β3-receptorsensitivity, and adenosine triphosphatase enzyme activity. Geneticfactors may include a mutation in the gene coding for the β3-adrenergicreceptor causing low β3-adrenergic activity which promotes obesity byslowing lipolysis and causing retention of lipids in fat cells.Moreover, as weight is lost by restricted energy intake, fat cellsshrink, reducing expression of leptin, a product of the ob gene. Asleptin levels fall, metabolic rate decreases, and appetite increases,thereby generally impeding further weight loss. Thus, obesity controlmedications are often formulated to reduce energy intake or suppressappetite, increase energy output or decrease the absorption of nutrientsby various different approaches.

[0006] Despite the current approaches for the treatment or prevention ofobesity, there remains a need in the art for improved compositions andtreatments for obesity.

SUMMARY OF THE INVENTION

[0007] One embodiment of the present invention provides a compositioncomprising (a) at least one obesity control medication; and (b) at leastone sterol absorption inhibitor and/or at least one 5α-stanol absorptioninhibitor or a pharmaceutically acceptable salt thereof or a solvatethereof.

[0008] Therapeutic combinations also are provided comprising: (a) afirst amount of at least one obesity control medication; and (b) asecond amount of at least one sterol absorption inhibitor and/or atleast one 5α-stanol absorption inhibitor or a pharmaceuticallyacceptable salt thereof or a solvate thereof, wherein the first amountand the second amount together comprise a therapeutically effectiveamount for the treatment or prevention of obesity or lowering aconcentration of a sterol or 5α-stanol in plasma of a subject.

[0009] Pharmaceutical compositions for the treatment or prevention ofobesity or lowering a concentration of a sterol or 5α-stanol in plasmaof a subject comprising administering a therapeutically effective amountof the above compositions or therapeutic combinations and apharmaceutically acceptable carrier also are provided.

[0010] Methods of treating or preventing obesity or lowering aconcentration of a sterol or 5α-stanol in plasma of a subject,comprising the step of administering to a subject in need of suchtreatment an effective amount of the above compositions or therapeuticcombinations also are provided.

[0011] Methods of treating or preventing obesity comprising the step ofadministering to a subject in need of such treatment an effective amountof a composition comprising at least one sterol absorption inhibitorand/or 5α-stanol absorption inhibitor also are provided.

[0012] A method of treating or preventing obesity is provided whichcomprises the step of administering to a subject in need of suchtreatment an effective amount of a composition comprising at least onesterol absorption inhibitor represented by Formula (II) below:

[0013] Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”

DETAILED DESCRIPTION

[0014] In one embodiment, the present invention is directed tocompositions, pharmaceutical compositions, therapeutic combinations,kits and methods of treatment using the same comprising (1) at least one(one or more) obesity control medication(s); and (2) at least one (oneor more) sterol absorption inhibitor(s) and/or at least one (one ormore) 5α-stanol absorption inhibitor(s), such as but not limited to,substituted azetidinone sterol absorption inhibitors or substitutedβ-lactam sterol absorption inhibitors discussed in detail below.

[0015] Many different agents are useful for the control or medicalmanagement of obesity. The different agents can be classified by theirmechanism of action, such as but not limited to, drugs that reduceenergy intake or suppress appetite, drugs that increase energyexpenditure and nutrient-partitioning agents.

[0016] Drugs that reduce energy intake include, in part, variouspharmacological agents, referred to as anorectic drugs, which are usedas adjuncts to behavioral therapy in weight reduction programs. Classesof anorectic drugs include, but are not limited to, noradrenergic andserotonergic agents. Noradrenergic medications may be described as thosemedications generally preserving the anorectic effects of amphetaminesbut with weaker stimulant activity. The noradrenergic drugs, exceptphenylpropanolamine, generally act through a centrally mediated pathwayin the hypothalamus that causes anorexia. Phenylpropanolamine, a racemicmixture of norephedrine esters, causes a release of norepinephrinethroughout the body and stimulates hypothalamic adrenoreceptors toreduce appetite.

[0017] Suitable noradrenergic agents include, but are not limited to,diethylpropion such as TENUATE® (1-propanone,2-(diethylamino)-1-phenyl-, hydrochloride) commercially available fromMerrell; mazindol (or5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol) such asSANOREX® commercially available from Novartis or MAZANOR® commerciallyavailable from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol,alpha-(1-aminoethyl)-, hydrochloride); phentermine (or Phenol,3-[[4,5-duhydro-1H-imidazol-2-yl)ethyl](4-methylphenyl)amino],monohydrochloride) such as ADIPEX-P® commercially available from Lemmon,FASTIN® commercially available from Smith-Kline Beecham and Ionamin®commercially available from Medeva; phendimetrazine (or(2S,3S)-3,4-Dimethyl-2phenylmorpholine L-(+)-tartrate (1:1)) such asMETRA® commercially available from Forest, PLEGINE® commerciallyavailable from Wyeth-Ayerst; PRELU-2® commercially available fromBoehringer Ingelheim, and STATOBEX® commercially available from Lemmon;phendamine tartrate such as THEPHORIN®(2,3,4,9-Tetrahydro-2-methyl-9-phenyl-1H-indenol[2,1-c]pyridineL-(+)-tartrate (1:1)) commercially available from Hoffmann-LaRoche;methamphetamine such as DESOXYN® Tablets ((S)—N,(alpha)-dimethylbenzeneethanamine hydrochloride) commercially availablefrom Abbott; and phendimetrazine tartrate such as BONTRIL® Slow-ReleaseCapsules (-3,4-Dimethyl-2-phenylmorpholine Tartrate) commerciallyavailable from Amarin.

[0018] Suitable non-limiting serotonergic agents include sibutraminesuch as MERIDIA® Capsules (a racemic mixture of the (+) and (−)enantiomers of cyclobutanemethanamine,1-(4-chlorophenyl)-N,N-dimethyl-(alpha)-(2-methylpropyl)-,hydrochloride, monohydrate) commercially available from Knoll,fenfluramine such as Pondimin® (Benzeneethanamine,N-ethyl-alpha-methyl-3-(trifluoromethyl)-, hydrochloride) commerciallyavailable from Robbins; dexfenfluramine such as Redux®(Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)-,hydrochloride) commercially available from Interneuron. Fenfluramine anddexfenfluramine stimulate release of serotonin and inhibit its reuptake.Sibutramine inhibits the reuptake of serotonin, norepinephrine anddopamine, but does not stimulate secretion of serotonin.

[0019] Other serotonergic agents useful with the practice of the presentinvention include, but are not limited to, certain auoretic gene 5HT1ainhibitors (brain, serotonin) such as carbidopa and benserazide asdisclosed by U.S. Pat. No. 6,207,699 which is incorporated herein byreference; and certain neurokinin 1 receptor antagonist and selectiveserotonin reuptake inhibitors including fluoxetine, fluvoxamine,paroxtine, sertraline and other useful compounds as disclosed by U.S.Pat. No. 6,162,805 which is incorporated herein by reference.

[0020] Other useful compounds for reducing energy intake include, butare not limited to, certain aryl-substituted cyclobutylalkylamines asdisclosed by U.S. Pat. No. 6,127,424 which is incorporated herein byreference; certain trifluoromethylthiophenylethylamine derivatives asdisclosed by U.S. Pat. No. 4,148,923 which is incorporated herein byreference; certain compounds as disclosed by U.S. Pat. No. 6,207,699which is incorporated herein by reference; certain kainite or AMPAreceptor antagonists as disclosed by U.S. Pat. No. 6,191,117 which isincorporated herein by reference; certain neuropeptide receptor subtype5 as disclosed by U.S. Pat. No. 6,140,354 which is incorporated hereinby reference; and certain alpha-blocking agents as disclosed by U.S.Pat. No. 4,239,763 which is incorporated herein by reference.

[0021] Moreover, several peptides and hormones regulate feedingbehavior. For example, cholecystokinin and serotonin act to decreaseappetite and food intake. Leptin, a hormone produced by fat cells,controls food intake and energy expenditure. In obese persons who arelosing weight without medications, a decrease in weight is associatedwith a decrease in circulating levels of leptin, suggesting its role inweight homeostasis. Obese patients with high leptin levels are thoughtto have peripheral leptin resistance secondary to the down-regulation ofleptin receptors. Non-limiting examples of useful compounds affectingfeeding behavior include certain leptin-lipolysis stimulated receptorsas disclosed by WO 01/21647 which is incorporated herein by reference;certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970which is incorporated herein by reference; certain compounds havingnucleotide sequences of the mahogany gene as disclosed by WO 00/05373which is incorporated herein by reference; certain sapogenin compoundsas disclosed by U.S. Pat. No. 4,680,289 which is incorporated herein byreference.

[0022] Other useful compounds include certain gamma peroxisomeproliferator activated receptor (PPAR) agonists as disclosed by WO01/30343 and U.S. Pat. No. 6,033,656 which are incorporated herein byreference and certain polypeptides such as fibroblast growth factor-10polypeptides as disclosed by WO 01/18210 which is incorporated herein byreference.

[0023] Moreover, monoamine oxidase inhibitors that decrease energyintake or increase energy expenditure are useful with the practice ofthe present invention. Suitable, but non-limiting examples of monoamineoxidase inhibitors include befloxatone, moclobemide, brofaromine,phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine,sercloremine, bazinaprine, lazabemide, milacemide, caroxazone and othercertain compounds as disclosed by WO 01/12176 which is incorporatedherein by reference.

[0024] Certain compounds that increase lipid metabolism are also usefulwith the practice of the present invention. Such compounds include, butare not limited to, useful evodiamine compounds as disclosed by U.S.Pat. No. 6,214,831 which is incorporated herein by reference.

[0025] Nutrient partitioning agents and digestive inhibitors are anotherstrategy in the treatment of obesity by interfering with the breakdown,digestion or absorption of dietary fat in the gastrointestinal tract.Gastric and pancreatic lipases aid in the digestion of dietarytriglycerides by forming them into free fatty acids that are thenabsorbed in the small intestine. Inhibition of these enzymes leads toinhibition of the digestion of dietary triglycerides. Non-limitingexamples include a lipase inhibitor, orlistat, such as XENICAL® Capsules((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester) commerciallyavailable from Roche Laboratories and certain benzoxazinone compounds asdescribed by WO 00/40247 which is incorporated herein by reference.

[0026] Agents that increase energy expenditure are also referred to asthermogenic medications. Non-limiting examples of suitable thermogenicmedications include ephedrine, and xanthines, such as caffeine andtheophylline, selective β3-adrenergic agonists for example certaincompounds in U.S. Pat. No. 4,626,549 which is incorporated by referenceherein, α-2-adrenergic and growth hormones compounds as described inU.S. Pat. Nos. 4,937,267 and 5,120,713 which are incorporated byreference herein; and suitable herbal extracts such as Thermo-E Capletscommercially available from AdvoCare which contains ephedra.

[0027] Generally, a total dosage of the above-described obesity controlagents or medications can range from 1 to 3,000 mg/day, preferably fromabout 1 to 1,000 mg/day and more preferably from about 1 to 200 mg/dayin single or 2-4 divided doses. The exact dose, however, is determinedby the attending clinician and is dependent on such factors as thepotency of the compound administered, the age, weight, condition andresponse of the patient.

[0028] The term “therapeutically effective amount” means that amount ofa therapeutic agent of the composition, such as the obesity controlmedication, sterol or 5α-stanol absorption inhibitor(s) and otherpharmacological or therapeutic agents described below, that will elicita biological or medical response of a tissue, system, or subject that isbeing sought by the administrator (such as a researcher, doctor orveterinarian) which includes alleviation of the symptoms of thecondition or disease being treated and the prevention, slowing orhalting of progression of the condition (such as obesity or a vascularcondition). As used herein, “vascular” means relating to blood vessels,including but not limited to arteries and/or veins, and includescardiovascular, cerebrovascular, peripheral vascular and combinationsthereof.

[0029] Examples of suitable subjects that can be treated according tothe methods of the present invention include mammals, such as humans ordogs, and other animals.

[0030] As used herein, “combination therapy” or “therapeuticcombination” means the administration of two or more therapeutic agents,such as obesity control medication and sterol and/or 5α-stanolabsorption inhibitor(s), to prevent or treat obesity. Suchadministration includes coadministration of these therapeutic agents ina substantially simultaneous manner, such as in a single tablet orcapsule having a fixed ratio of active ingredients or in multiple,separate capsules for each therapeutic agent. Also, such administrationincludes use of each type of therapeutic agent in a sequential manner.In either case, the treatment using the combination therapy will providebeneficial effects in treating obesity. A potential advantage of thecombination therapy disclosed herein may be a reduction in the requiredamount of an individual therapeutic compound or the overall total amountof therapeutic compounds that are effective in treating obesity. Byusing a combination of therapeutic agents, the side effects of theindividual compounds can be reduced as compared to a monotherapy, whichcan improve patient compliance. Also, therapeutic agents can be selectedto provide a broader range of complimentary effects or complimentarymodes of action.

[0031] As discussed above, in one embodiment, the compositions,pharmaceutical compositions and therapeutic combinations of the presentinvention can comprise one or more sterol or 5α-stanol absorptioninhibitors, for example substituted azetidinone sterol absorptioninhibitors or substituted β-lactam sterol absorption inhibitorsdiscussed in detail below. As used herein, “sterol absorption inhibitor”means a compound capable of inhibiting the absorption of one or moresterols, including but not limited to cholesterol or phytosterols (suchas sitosterol, campesterol, stigmasterol and avenosterol) whenadministered in a therapeutically effective (sterol absorptioninhibiting) amount to a subject. “5α-stanol absorption inhibitor” meansa compound capable of inhibiting the absorption of one or more5α-stanols (such as cholestanol, 5α-campestanol, 5α-sitostanol) whenadministered in a therapeutically effective (5α-stanol absorptioninhibiting) amount to a subject. Mixtures of sterol absorptioninhibitor(s) and 5α-stanol absorption inhibitor(s) are contemplated.

[0032] In a preferred embodiment, sterol and/or 5α-stanol absorptioninhibitors useful in the compositions, therapeutic combinations andmethods of the present invention are represented by Formula (I) below:

[0033] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein, in Formula (I) above:

[0034] Ar¹ and Ar² are independently selected from the group consistingof aryl and R⁴-substituted aryl;

[0035] Ar³ is aryl or R⁵-substituted aryl;

[0036] X, Y and Z are independently selected from the group consistingof —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-;

[0037] R and R² are independently selected from the group consisting of—OR⁶, —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷;

[0038] R¹ and R³ are independently selected from the group consisting ofhydrogen, lower alkyl and aryl;

[0039] q is 0 or 1; r is 0 or 1; m, n and p are independently selectedfrom 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, andthe sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided thatwhen p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;

[0040] R⁴ is 1-5 substituents independently selected from the groupconsisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN,—NO₂ and halogen;

[0041] R⁵ is 1-5 substituents independently selected from the groupconsisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

[0042] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and

[0043] R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

[0044] Preferably, R⁴ is 1-3 independently selected substituents, and R⁵is preferably 1-3 independently selected substituents.

[0045] As used herein, the term “alkyl” or “lower alkyl” means straightor branched alkyl chains having from 1 to 6 carbon atoms and “alkoxy”means alkoxy groups having 1 to 6 carbon atoms. Non-limiting examples oflower alkyl groups include, for example methyl, ethyl, propyl, and butylgroups.

[0046] “Alkenyl” means straight or branched carbon chains having one ormore double bonds in the chain, conjugated or unconjugated. Similarly,“alkynyl” means straight or branched carbon chains having one or moretriple bonds in the chain. Where an alkyl, alkenyl or alkynyl chainjoins two other variables and is therefore bivalent, the terms alkylene,alkenylene and alkynylene are used.

[0047] “Cycloalkyl” means a saturated carbon ring of 3 to 6 carbonatoms, while “cycloalkylene” refers to a corresponding bivalent ring,wherein the points of attachment to other groups include all positionalisomers.

[0048] “Halogeno” refers to fluorine, chlorine, bromine or iodineradicals.

[0049] “Aryl” means phenyl, naphthyl, indenyl, tetrahydronaphthyl orindanyl.

[0050] “Phenylene” means a bivalent phenyl group, including ortho, metaand para-substitution.

[0051] The statements wherein, for example, R, R¹, R² and R³, are saidto be independently selected from a group of substituents, mean that R,R¹, R² and R³ are independently selected, but also that where an R, R¹,R² and R³ variable occurs more than once in a molecule, each occurrenceis independently selected (e.g., if R is —OR⁶, wherein R⁶ is hydrogen,R² can be —OR⁶ wherein R⁶ is lower alkyl). Those skilled in the art willrecognize that the size and nature of the substituent(s) will affect thenumber of substituents that can be present. Compounds of the inventionhave at least one asymmetrical carbon atom and therefore all isomers,including enantiomers, stereoisomers, rotamers, tautomers and racematesof the compounds of Formulae I-XII are contemplated as being part ofthis invention. The invention includes d and l isomers in both pure formand in admixture, including racemic mixtures. Isomers can be preparedusing conventional techniques, either by reacting optically pure oroptically enriched starting materials or by separating isomers of acompound of the Formulas I-XII. Isomers may also include geometricisomers, e.g., when a double bond is present.

[0052] Those skilled in the art will appreciate that for some of thecompounds of the Formulas I-XII, one isomer will show greaterpharmacological activity than other isomers.

[0053] Compounds of the invention with an amino group can formpharmaceutically acceptable salts with organic and inorganic acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those in the art. The salt isprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt. The free base form may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous sodium bicarbonate. The free base formdiffers from its respective salt form somewhat in certain physicalproperties, such as solubility in polar solvents, but the salt isotherwise equivalent to its respective free base forms for purposes ofthe invention.

[0054] Certain compounds of the invention are acidic (e.g., thosecompounds which possess a carboxyl group). These compounds formpharmaceutically acceptable salts with inorganic and organic bases.Examples of such salts are the sodium, potassium, calcium, aluminum,gold and silver salts. Also included are salts formed withpharmaceutically acceptable amines such as ammonia, alkyl amines,hydroxyalkylamines, N-methylglucamine and the like.

[0055] As used herein, “solvate” means a molecular or ionic complex ofmolecules or ions of solvent with those of solute (for example, one ormore compounds of Formulae I-XII, isomers of the compounds of FormulaeI-XII, or prodrugs of the compounds of Formulae I-XII). Non-limitingexamples of useful solvents include polar, protic solvents such as waterand/or alcohols (for example methanol).

[0056] Prodrugs of the compounds of Formulae I-XII are contemplated asbeing part of this invention. As used herein, “prodrug” means compoundsthat are drug precursors which, following administration to a patient,release the drug in vivo via some chemical or physiological process(e.g., a prodrug on being brought to the physiological pH or throughenzyme action is converted to the desired drug form).

[0057] Preferred compounds of Formula (I) are those in which Ar¹ isphenyl or R⁴-substituted phenyl, more preferably (4-R⁴)-substitutedphenyl. Ar² is preferably phenyl or R⁴-substituted phenyl, morepreferably (4-R⁴)-substituted phenyl. Ar³ is preferably R⁵-substitutedphenyl, more preferably (4-R⁵)-substituted phenyl. When Ar¹ is(4-R⁴)-substituted phenyl, R⁴ is preferably a halogen. When Ar² and Ar³are R⁴- and R⁵-substituted phenyl, respectively, R⁴ is preferablyhalogen or —OR⁶ and R⁵ is preferably —OR⁶, wherein R⁶ is lower alkyl orhydrogen. Especially preferred are compounds wherein each of Ar¹ and Ar²is 4-fluorophenyl and Ar³ is 4-hydroxyphenyl or 4-methoxyphenyl.

[0058] X, Y and Z are each preferably —CH₂—. R¹ and R³ are eachpreferably hydrogen. R and R² are preferably —OR⁶ wherein R⁶ ishydrogen, or a group readily metabolizable to a hydroxyl (such as—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷, defined above).

[0059] The sum of m, n, p, q and r is preferably 2, 3 or 4, morepreferably 3. Preferred are compounds wherein m, n and r are each zero,q is 1 and p is 2.

[0060] Also preferred are compounds of Formula (I) in which p, q and nare each zero, r is 1 and m is 2 or 3. More preferred are compoundswherein m, n and r are each zero, q is 1, p is 2, Z is —CH₂— and R is—OR⁶, especially when R⁶ is hydrogen.

[0061] Also more preferred are compounds of Formula (I) wherein p, q andn are each zero, r is 1, m is 2, X is —CH₂— and R² is —OR⁶, especiallywhen R⁶ is hydrogen.

[0062] Another group of preferred compounds of Formula (I) is that inwhich Ar¹ is phenyl or R⁴-substituted phenyl, Ar² is phenyl orR⁴-substituted phenyl and Ar³ is R⁵-substituted phenyl. Also preferredare compounds in which Ar¹ is phenyl or R⁴-substituted phenyl, Ar² isphenyl or R⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, and thesum of m, n, p, q and r is 2, 3 or 4, more preferably 3. More preferredare compounds wherein Ar¹ is phenyl or R⁴-substituted phenyl, Ar² isphenyl or R⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, andwherein m, n and r are each zero, q is 1 and p is 2, or wherein p, q andn are each zero, r is 1 and m is 2 or 3.

[0063] In a preferred embodiment, a sterol or 5α-stanol absorptioninhibitor of Formula (I) useful in the compositions, therapeuticcombinations and methods of the present invention is represented byFormula (II) (ezetimibe) below:

[0064] or a pharmaceutically acceptable salt or solvate thereof. Thecompound of Formula (II) can be in anhydrous or hydrated form.

[0065] Compounds of Formula I can be prepared by a variety of methodswell known to those skilled in the art, for example such as aredisclosed in U.S. Pat. Nos. 5,631,365, 5,767,115, 5,846,966, 6,207,822,U.S. patent application Ser. No. 10/105,710 filed Mar. 25, 2002 and PCTPatent Application WO 93/02048, each of which is incorporated herein byreference, and in the Example below. For example, suitable compounds ofFormula I can be prepared by a method comprising the steps of:

[0066] (a) treating with a strong base a lactone of the Formula A or B:

[0067] wherein R′ and R^(2′) are R and R², respectively, or are suitablyprotected hydroxy groups; Ar¹⁰ is Ar¹, a suitably protectedhydroxy-substituted aryl or a suitably protected amino-substituted aryl;and the remaining variables are as defined above for Formula I, providedthat in lactone of formula B, when n and r are each zero, p is 1-4;

[0068] (b) reacting the product of step (a) with an imine of the formula

[0069] wherein Ar²⁰ is Ar², a suitably protected hydroxy-substitutedaryl or a suitably protected amino-substituted aryl; and Ar³⁰ is Ar³, asuitably protected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl;

[0070] c) quenching the reaction with an acid;

[0071] d) optionally removing the protecting groups from R′, R^(2′),Ar¹⁰, Ar²⁰ and Ar³⁰, when present; and

[0072] e) optionally functionalizing hydroxy or amino substituents at R,R², Ar¹, Ar² and Ar³.

[0073] Using the lactones shown above, compounds of Formula IA and IBare obtained as follows:

[0074] wherein the variables are as defined above; and

[0075] wherein the variables are as defined above.

[0076] Alternative sterol or 5α-stanol absorption inhibitors useful inthe compositions, therapeutic combinations and methods of the presentinvention are represented by Formula (III) below:

[0077] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein, in Formula (III) above:

[0078] Ar¹ is R³-substituted aryl;

[0079] Ar² is R⁴-substituted aryl;

[0080] Ar³ is R⁵-substituted aryl;

[0081] Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-;

[0082] A is selected from —O—, —S—, —S(O)— or —S(O)₂—;

[0083] R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O;

[0084] q is 1, 2 or 3;

[0085] p is 0, 1, 2, 3 or 4;

[0086] R⁵ is 1-3 substituents independently selected from the groupconsisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl,—NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-loweralkyl, m-lower alkyl, -(lower alkylene)-COOR⁶, and —CH═CH—COOR⁶;

[0087] R³ and R⁴ are independently 1-3 substituents independentlyselected from the group consisting of R⁵, hydrogen, p-lower alkyl, aryl,—NO₂, —CF₃ and p-halogeno;

[0088] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

[0089] Preferred compounds of Formula I include those in which Ar¹ isR³-substituted phenyl, especially (4-R³)-substituted phenyl. Ar² ispreferably R⁴-substituted phenyl, especially (4-R⁴)-substituted phenyl.Ar³ is preferably R⁵-substitiuted phenyl, especially (4-R⁵)-substitutedphenyl. Mono-substitution of each of Ar¹, Ar² and Ar³ is preferred.

[0090] Y and Z are each preferably —CH₂—. R² is preferably hydrogen. R¹is preferably —OR⁶ wherein R⁶ is hydrogen, or a group readilymetabolizable to a hydroxyl (such as —O(CO)R⁶, —O(CO)OR⁹ and—O(CO)NR⁶R⁷, defined above). Also preferred are compounds wherein R¹ andR² together are ═O.

[0091] The sum of q and p is preferably 1 or 2, more preferably 1.Preferred are compounds wherein p is zero and q is 1. More preferred arecompounds wherein p is zero, q is 1, Y is —CH₂— and R¹ is —OR⁶,especially when R⁶ is hydrogen.

[0092] Another group of preferred compounds is that in which Ar¹ isR³-substituted phenyl, Ar² is R⁴-substituted phenyl and Ar³ isR⁵-substituted phenyl.

[0093] Also preferred are compounds wherein Ar¹ is R³-substitutedphenyl, Ar² is R⁴-substituted phenyl, Ar³ is R⁵-substituted phenyl, andthe sum of p and q is 1 or 2, especially 1. More preferred are compoundswherein Ar¹ is R³-substituted phenyl, Ar² is R⁴-substituted phenyl, Ar³is R⁵-substituted phenyl, p is zero and q is 1.

[0094] A is preferably —O—.

[0095] R³ is preferably —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷,S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, NO₂ or halogeno. A more preferreddefinition for R³ is halogeno, especially fluoro or chloro.

[0096] R⁴ is preferably hydrogen, lower alkyl, —OR⁶, —O(CO)R⁶,—O(CO)OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, COR⁶ or halogeno, wherein R⁶ and R⁷ arepreferably independently hydrogen or lower alkyl, and R⁹ is preferablylower alkyl. A more preferred definition for R⁴ is hydrogen or halogeno,especially fluoro or chloro.

[0097] R⁵ is preferably —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷,-(lower alkylene)-COOR⁶ or —CH═CH—COOR⁶, wherein R⁶ and R⁷ arepreferably independently hydrogen or lower alkyl, and R⁹ is preferablylower alkyl. A more preferred definition for R⁵ is —OR⁶, -(loweralkylene)-COOR⁶ or —CH═CH—COOR⁶, wherein R⁶ is preferably hydrogen orlower alkyl.

[0098] Methods for making compounds of Formula III are well known tothose skilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,688,990, which is incorporated herein byreference.

[0099] In another embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formula (IV):

[0100] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein, in Formula (IV) above:

[0101] A is selected from the group consisting of R²-substitutedheterocycloalkyl, R²-substituted heteroaryl, R²-substituted benzofusedheterocycloalkyl, and R²-substituted benzofused heteroaryl;

[0102] Ar¹ is aryl or R³-substituted aryl;

[0103] Ar² is aryl or R⁴-substituted aryl;

[0104] Q is a bond or, with the 3-position ring carbon of theazetidinone, forms the spiro group

[0105] R¹ is selected from the group consisting of:

[0106] —(CH₂)_(q)—, wherein q is 2-6, provided that when Q forms a spiroring, q can also be zero or 1;

[0107] —(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene,—NR⁸— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of eand r is 1-6;

[0108] —(C₂-C₆ alkenylene)-; and

[0109] —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is1-5 and g is 0-5, provided that the sum of f and g is 1-6;

[0110] R⁵ is selected from:

[0111] R⁶ and R⁷ are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆)alkyl), —CH═CH— and —C(C₁-C₆alkyl)=CH—; or R⁵ together with an adjacent R⁶, or R⁵ together with anadjacent R⁷, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group;

[0112] a and b are independently 0, 1, 2 or 3, provided both are notzero; provided that when R⁶ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, a is 1;provided that when R⁷ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, b is 1;provided that when a is 2 or 3, the R⁶'s can be the same or different;and provided that when b is 2 or 3, the R⁷'s can be the same ordifferent;

[0113] and when Q is a bond, R¹ also can be selected from:

[0114] where M is —O—, —S—, —S(O)— or —S(O)₂—;

[0115] X, Y and Z are independently selected from the group consistingof —CH₂—, —CH(C₁-C₆ alkyl)- and —C(di-(C₁-C₆)alkyl);

[0116] R¹⁰ and R¹² are independently selected from the group consistingof —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵;

[0117] R¹¹ and R¹³ are independently selected from the group consistingof hydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, orR¹² and R¹³ together are ═O;

[0118] d is 1, 2 or 3;

[0119] h is 0, 1, 2, 3 or 4;

[0120] s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;provided that at least one of s and t is 1, and the sum of m, n, p, sand t is 1-6; provided that when p is 0 and t is 1, the sum of m, s andn is 1-5; and provided that when p is 0 and s is 1, the sum of m, t andn is 1-5;

[0121] v is 0 or 1;

[0122] j and k are independently 1-5, provided that the sum of j, k andv is 1-5;

[0123] R² is 1-3 substituents on the ring carbon atoms selected from thegroup consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substitutedaryl, R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆ alkylene)-, NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-, —NHC(O)R¹⁶, OH, C₁-C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

[0124] and, where R² is a substituent on a substitutable ring nitrogen,it is hydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆) alkoxy, aryloxy,(C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

[0125] wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—;

[0126] R³ and R⁴ are independently selected from the group consisting of1-3 substituents independently selected from the group consisting of(C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴,—O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵, —NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹,—NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵, —COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶,—O(CH₂)₁₋₁₀—COOR¹⁴, —O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴,—CH═CH—COOR¹⁴, —CF₃, —CN, —NO₂ and halogen;

[0127] R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁴ or—COOR¹⁴;

[0128] R⁹ and R¹⁷ are independently 1-3 groups independently selectedfrom the group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,—COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno;

[0129] R¹⁴ and R¹⁵ are independently selected from the group consistingof hydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

[0130] R¹⁶ is (C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl;

[0131] R¹⁸ is hydrogen or (C₁-C₆)alkyl; and

[0132] R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy.

[0133] As used in Formula (IV) above, “A” is preferably anR²-substituted, 6-membered heterocycloalkyl ring containing 1 or 2nitrogen atoms. Preferred heterocycloalkyl rings are piperidinyl,piperazinyl and morpholinyl groups. The ring “A” is preferably joined tothe phenyl ring through a ring nitrogen. Preferred R² substituents arehydrogen and lower alkyl. R¹⁹ is preferably hydrogen.

[0134] Ar² is preferably phenyl or R⁴-phenyl, especially(4-R⁴)-substituted phenyl. Preferred definitions of R⁴ are-lower alkoxy,especially methoxy, and halogeno, especially fluoro.

[0135] Ar¹ is preferably phenyl or R³-substituted phenyl, especially(4-R³)-substituted phenyl.

[0136] There are several preferred definitions for the —R¹-Q-combination of variables:

[0137] Q is a bond and R¹ is lower alkylene, preferably propylene;

[0138] Q is a spiro group as defined above, wherein preferably R⁶ and R⁷are each ethylene and R⁵ is

[0139] Q is a bond and R¹ is

[0140] wherein the variables are chosen such that R¹ is —O—CH₂—CH(OH)—;

[0141] Q is a bond and R¹ is

[0142] wherein the variables are chosen such that R¹ is —CH(OH)—(CH₂)₂—;and

[0143] Q is a bond and R¹ is

[0144] wherein the variables are chosen such that R¹ is—CH(OH)—CH₂—S(O)₀₋₂—.

[0145] Methods for making compounds of Formula IV are well known tothose skilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,656,624, which is incorporated herein byreference.

[0146] In another embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formula (V):

[0147] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein, in Formula (V) above:

[0148] Ar¹ is aryl, R¹⁰-substituted aryl or heteroaryl;

[0149] Ar² is aryl or R⁴-substituted aryl;

[0150] Ar³ is aryl or R⁵-substituted aryl;

[0151] X and Y are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-;

[0152] R is —OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen,lower alkyl or aryl; or R and R¹ together are ═O;

[0153] q is 0 or 1;

[0154] r is 0, 1 or 2;

[0155] m and n are independently 0, 1, 2, 3, 4 or 5; provided that thesum of m, n and q is 1, 2, 3, 4 or 5;

[0156] R⁴ is 1-5 substituents independently selected from the groupconsisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

[0157] R⁵ is 1-5 substituents independently selected from the groupconsisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶-CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶;

[0158] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl;

[0159] R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and

[0160] R¹⁰ is 1-5 substituents independently selected from the groupconsisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen.

[0161] Within the scope of Formula V, there are included two preferredstructures. In Formula VA, q is zero and the remaining variables are asdefined above, and in Formula VB, q is 1 and the remaining variables areas defined above:

[0162] R⁴, R⁵ and R¹⁰ are each preferably 1-3 independently selectedsubstituents as set forth above. Preferred are compounds of Formula (V)wherein Ar¹ is phenyl, R¹⁰-substituted phenyl or thienyl, especially(4-R¹⁰)-substituted phenyl or thienyl. Ar² is preferably R⁴-substitutedphenyl, especially (4-R⁴)-substituted phenyl. Ar³ is preferably phenylor R⁵-substituted phenyl, especially (4-R⁵)-substituted phenyl. When Ar¹is R¹⁰-substituted phenyl, R¹⁰ is preferably halogeno, especiallyfluoro. When Ar² is R⁴-substituted phenyl, R⁴ is preferably —OR⁶,especially wherein R⁶ is hydrogen or lower alkyl. When Ar³ isR⁵-substituted phenyl, R⁵ is preferably halogeno, especially fluoro.Especially preferred are compounds of Formula (V) wherein Ar¹ is phenyl,4-fluorophenyl or thienyl, Ar² is 4-(alkoxy or hydroxy)phenyl, and Ar³is phenyl or 4-fluorophenyl.

[0163] X and Y are each preferably —CH₂—. The sum of m, n and q ispreferably 2, 3 or 4, more preferably 2. When q is 1, n is preferably 1to 5.

[0164] Preferences for X, Y, Ar¹, Ar² and Ar³ are the same in each ofFormulae (VA) and (VB).

[0165] In compounds of Formula (VA), the sum of m and n is preferably 2,3 or 4, more preferably 2. Also preferred are compounds wherein the sumof m and n is 2, and r is 0 or 1.

[0166] In compounds of Formula (VB), the sum of m and n is preferably 1,2 or 3, more preferably 1. Especially preferred are compounds wherein mis zero and n is 1. R¹ is preferably hydrogen and R is preferably —OR⁶wherein R⁶ is hydrogen, or a group readily metabolizable to a hydroxyl(such as —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷, defined above), or R andR¹ together form a ═O group.

[0167] Methods for making compounds of Formula V are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,624,920, which is incorporated herein byreference.

[0168] In another embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formula (VI):

[0169] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein:

[0170] R₁ is

[0171] R₂ and R₃ are independently selected from the group consistingof:

[0172] —CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and—C(lower alkyl)=CH—; or

[0173] R₁ together with an adjacent R₂, or R₁ together with an adjacentR₃, form a —CH═CH— or a —CH═C(lower alkyl)- group;

[0174] u and v are independently 0, 1, 2 or 3, provided both are notzero; provided that when R₂ is —CH═CH— or —C(lower alkyl)=CH—, v is 1;provided that when R₃ is —CH═CH— or —C(lower alkyl)=CH—, u is 1;provided that when v is 2 or 3, the R₂'s can be the same or different;and provided that when u is 2 or 3, the R₃'s can be the same ordifferent;

[0175] R₄ is selected from B—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4or 5; B—(CH₂)_(q)—, wherein q is 0, 1, 2, 3, 4, 5 or 6;B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—, —C(O)—, phenylene, —N(R₈)—or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5,provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B—(C₂-C₆alkenylene)-; B—(C₄-C₆ alkadienylene)-; B—(CH₂)_(t)-Z-(C₂-C₆alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or3, provided that the sum of t and the number of carbon atoms in thealkenylene chain is 2, 3, 4, 5 or 6; B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein Vis C₃-C₆ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B-(C2-C6 alkenylene)-V—(CH₂)_(t)—,wherein V and t are as defined above, provided that the sum of t and thenumber of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(a)-Z-(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z and V are as definedabove and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, providedthat the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH₂)_(s)—,wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or6; or

[0176] R₁ and R₄ together form the group

[0177] B is selected from indanyl, indenyl, naphthyl,tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, whereinheteroaryl is selected from the group consisting of pyrrolyl, pyridinyl,pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl,thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls,the N-oxides thereof, or

[0178] W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂, —N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

[0179] for substitution on ring carbon atoms, and the substituents onthe substituted heteroaryl ring nitrogen atoms, when present, areselected from the group consisting of lower alkyl, lower alkoxy,—C(O)OR₁₀, —C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-loweralkylenyloxy-, —S(O)₂NH₂ and 2-(trimethylsilyl)-ethoxymethyl;

[0180] R₇ is 1-3 groups independently selected from the group consistingof lower alkyl, lower alkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno;

[0181] R₈ and R₉ are independently selected from H or lower alkyl;

[0182] R₁₀ is selected from lower alkyl, phenyl, R₇-phenyl, benzyl orR₇-benzyl;

[0183] R₁₁ is selected from OH, lower alkyl, phenyl, benzyl, R₇-phenylor R₇-benzyl;

[0184] R₁₂ is selected from H, OH, alkoxy, phenoxy, benzyloxy,

[0185] —N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl;

[0186] R₁₃ is selected from —O—, —CH₂—, —NH—, —N(lower alkyl)- or—NC(O)R₁₉;

[0187] R_(15,) R₁₆ and R₁₇ are independently selected from the groupconsisting of H and the groups defined for W; or R₁₅ is hydrogen and R₁₆and R₁₇, together with adjacent carbon atoms to which they are attached,form a dioxolanyl ring;

[0188] R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and

[0189] R₂₀ and R₂₁ are independently selected from the group consistingof phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl,indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl,W-substituted heteroaryl, benzofused heteroaryl, W-substitutedbenzofused heteroaryl and cyclopropyl, wherein heteroaryl is as definedabove.

[0190] One group of preferred compounds of Formula VI is that in whichR₂₁ is selected from phenyl, W-substituted phenyl, indanyl,benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl,pyrimidinyl, quinolyl or cyclopropyl,

[0191] wherein W is lower alkyl, lower alkoxy, OH, halogeno, —N(R₈)(R₉),—NHC(O)OR₁₀, —NHC(O)R₁₀, NO₂, —CN, —N₃, —SH, —S(O)₀₋₂-(lower alkyl),—COOR₁₉, —CON(R₈)(R₉), —COR₁₂, phenoxy, benzyloxy, —OCF₃, —CH═C(O)R₁₂ ortert-butyldimethylsilyloxy, wherein R₈, R₉, R₁₀, R₁₂ and R₁₉ are asdefined for Formula IV. When W is 2 or 3 substituents, the substituentscan be the same or different.

[0192] Another group of preferred compounds of Formula VI is that inwhich R₂₀ is phenyl or W-substituted phenyl, wherein preferred meaningsof W are as defined above for preferred definitions of R₂₁.

[0193] More preferred are compounds of Formula VI wherein R₂₀ is phenylor W-substituted phenyl and R₂₁ is phenyl, W-substituted phenyl,indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl,pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; W is lower alkyl, loweralkoxy, OH, halogeno, —N(R₈)(R₉), —NHC(O)OR₁₀, —NHC(O)R₁₀, NO₂, —CN,—N₃, —SH, —S(O)₀₋₂-(lower alkyl), —COOR₁₉, —CON(R₈)(R₉), —COR₁₂,phenoxy, benzyloxy, —CH═CHC(O)R₁₂, —OCF₃ ortert-butyl-dimethyl-silyloxy, wherein when W is 2 or 3 substituents, thesubstituents can be the same or different, and wherein R₈, R₉, R₁₀, R₁₂and R₁₉ are as defined in Formula VI.

[0194] Also preferred are compounds of Formula VI wherein R₁ is

[0195] Another group of preferred compounds of Formula VI is in which R₂and R₃ are each —CH₂— and the sum of u and v is 2, 3 or 4, with u=v=2being more preferred.

[0196] R₄ is preferably B—(CH₂)_(q)— or B—(CH₂)_(e)-Z-(CH₂)_(r)—,wherein B, Z, q, e and r are as defined above. B is preferably

[0197] wherein R₁₆ and R₁₇ are each hydrogen and wherein R₁₅ ispreferably H, OH, lower alkoxy, especially methoxy, or halogeno,especially chloro.

[0198] Preferably Z is —O—, e is 0, and r is 0.

[0199] Preferably q is 0-2.

[0200] R₂₀ is preferably phenyl or W-substituted phenyl.

[0201] Preferred W substituents for R₂₀ are lower alkoxy, especiallymethoxy and ethoxy, OH, and —C(O)R₁₂, wherein R₁₂ is preferably loweralkoxy.

[0202] Preferably R₂₁ is selected from phenyl, lower alkoxy-substitutedphenyl and F-phenyl.

[0203] Especially preferred are compounds of Formula VI wherein R₁ is

[0204] R₂ and R₃ are each —CH₂—, u=v=2, R₄ is B—(CH₂)_(q)—, wherein B isphenyl or phenyl substituted by lower alkoxy or chloro, q is 0-2, R₂₀ isphenyl, OH-phenyl, lower alkoxy-substituted phenyl or loweralkoxycarbonyl-substituted phenyl, and R₂₁ is phenyl, loweralkoxy-substituted phenyl or F-phenyl.

[0205] Methods for making compounds of Formula VI are well known tothose skilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,698,548, which is incorporated herein byreference.

[0206] In another embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formulas (VIIA) and (VIIB):

[0207] or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0208] A is —CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2;

[0209] B is

[0210] D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 andq is 2, 3 or 4;

[0211] E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds;

[0212] R is hydrogen, C₁-C₁₅ alkyl, straight or branched, saturated orcontaining one or more double bonds, or B—(CH₂)_(r)—, wherein r is 0, 1,2, or 3;

[0213] R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′) are independently selectedfrom the group consisting of hydrogen, lower alkyl, lower alkoxy,carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino, dilower alkylamino,—NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂;

[0214] R₄ is

[0215] wherein n is 0, 1, 2 or 3;

[0216] R₅ is lower alkyl; and

[0217] R₆ is OH, lower alkyl, phenyl, benzyl or substituted phenylwherein the substituents are 1-3 groups independently selected from thegroup consisting of lower alkyl, lower alkoxy, carboxy, NO₂, NH₂, OH,halogeno, lower alkylamino and dilower alkylamino; or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.

[0218] Preferred are compounds of Formula (VIIA) wherein R is hydrogen,saturated or mono-unsaturated C₁-C₁₀ alkyl or phenyl. Another group ofpreferred compounds of Formula (VIIA) is that in which D is propyl(i.e., —(CH₂)_(q)— and q is 3). A third group of preferred compounds ofFormula (VIIA) is that wherein R₄ is p-methoxyphenyl or2,4,6-trimethoxyphenyl. Still another group of preferred compounds ofFormula (VIIA) is that wherein A is ethylene or a bond (i.e.,—(CH₂)_(p)— wherein p is zero). R_(1′), R_(2′), and R_(3′) arepreferably each hydrogen, and preferably R₁ is hydrogen, hydroxy, nitro,lower alkoxy, amino or t-butoxycarbonyl-amino and R₂ and R₃ are eachhydrogen.

[0219] More preferred are compounds of Formula (VIIA) wherein R_(1′),R_(2′), and R_(3′) are each hydrogen; R₁ is hydrogen, hydroxy, nitro,lower alkoxy, amino or t-butoxycarbonyl-amino and R₂ and R₃ are eachhydrogen; R is hydrogen, ethyl or phenyl; D is propyl; R₄ isp-methoxyphenyl or 2,4,6-trimethoxyphenyl; and A is ethylene or a bond.

[0220] Preferred compounds of Formula (VIIA), wherein B′ is phenyl, areshown in the following table: D R A B R₄ —(CH₂)₃— H — p-MeO-p-MeO-phenyl phenyl —CH₂C(O)— phenyl — phenyl p-MeO-phenyl —(CH₂)₃— H —phenyl p-MeO-phenyl —(CH₂)₃— H — p-OH- p-MeO-phenyl phenyl —(CH₂)₃— Hethylene p-MeO- p-MeO-phenyl phenyl —(CH₂)₃— H — 3-MeO- p-MeO-phenylphenyl —(CH₂)₃— ethyl — phenyl p-MeO-phenyl —(CH₂)₃— phenyl — phenylp-MeO-phenyl —(CH₂)₃— ethyl — phenyl 2,4,6-tri-MeO- phenyl —(CH₂)₃—methyl — phenyl p-MeO-phenyl —(CH₂)₃— H — p-NH₂- p-MeO-phenyl phenyl

[0221] The first-listed compound in the above table having the (3R,4S)absolute stereochemistry is more preferred.

[0222] Preferred compounds of Formula (VIIB) are those wherein R ishydrogen, methyl, ethyl, phenyl or phenylpropyl. Another group ofpreferred compounds of Formula (VIIB) is that wherein R₄ isp-methoxyphenyl or 2,4,6-trimethoxyphenyl. Still another group ofpreferred compounds of Formula (VIIB) is that wherein A is ethylene or abond. Yet another group of preferred compounds of Formula (VIIB) is thatwherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably R₁, R₂ and R₃are each hydrogen.

[0223] More preferred compounds of Formula (VIIB) are those wherein R ishydrogen, methyl, ethyl, phenyl or phenylpropyl; R₄ is p-methoxyphenylor 2,4,6-trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoylor 7-Z-hexadecenyl; and R₁, R₂ and R₃ are each hydrogen.

[0224] A preferred compound of Formula (VIIB) is that wherein E isdecyl, R is hydrogen, B-A is phenyl and R₄ is p-methoxyphenyl.

[0225] In another embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions and methods of the present invention arerepresented by Formula (VIII):

[0226] or a pharmaceutically acceptable salt thereof or a solvatethereof, wherein, in Formula (VIII) above,

[0227] R²⁶ is H or OG¹;

[0228] G and G¹ are independently selected from the group consisting of

[0229] provided that when R²⁶ is H or OH, G is not H;

[0230] R, R^(a) and R^(b) are independently selected from the groupconsisting of H, —OH, halogeno, —NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxyor —W—R³⁰;

[0231] W is independently selected from the group consisting of—NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and—O—C(S)—N(R³¹)—;

[0232] R² and R⁶ are independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl(C₁-C₆)alkyl;

[0233] R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are independently selected fromthe group consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,—C(O)(C₁-C₆)alkyl and —C(O)aryl;

[0234] R³⁰ is selected from the group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl;

[0235] R³¹ is selected from the group consisting of H and (C₁-C₄)alkyl;

[0236] T is selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

[0237] R³² is independently selected from 1-3 substituents independentlyselected from the group consisting of halogeno, (C₁-C₄)alkyl, —OH,phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy, oxo,(C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

[0238] Ar¹ is aryl or R¹⁰-substituted aryl;

[0239] Ar² is aryl or R¹¹-substituted aryl;

[0240] Q is a bond or, with the 3-position ring carbon of theazetidinone, forms the spiro group

[0241] R¹ is selected from the group consisting of

[0242] —(CH₂)_(q)—, wherein q is 2-6, provided that when Q forms a spiroring, q can also be zero or 1;

[0243] —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,—NR²²— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of eand r is 1-6;

[0244] —(C₂-C₆)alkenylene-; and

[0245] —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is1-5 and g is 0-5, provided that the sum of f and g is 1-6;

[0246] R¹² is

[0247] R¹³ and R¹⁴ are independently selected from the group consistingof

[0248] —CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆)alkyl), —CH═CH— and—C(C₁-C₆ alkyl)=CH—; or R¹² together with an adjacent R¹³, or R¹²together with an adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)-group;

[0249] a and b are independently 0, 1, 2 or 3, provided both are notzero;

[0250] provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, a is 1;

[0251] provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, b is 1;

[0252] provided that when a is 2 or 3, the R¹³'s can be the same ordifferent; and

[0253] provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent;

[0254] and when Q is a bond, R¹ also can be:

[0255] X, Y and Z are independently selected from the group consistingof —CH₂—, —CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl);

[0256] R¹⁰ and R¹¹ are independently selected from the group consistingof 1-3 substituents independently selected from the group consisting of(C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹,—O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵,—NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹,—O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆ alkylene)-COOR¹⁹,—CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen;

[0257] R¹⁵ and R¹⁷ are independently selected from the group consistingof —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰;

[0258] R¹⁶ and R¹⁸ are independently selected from the group consistingof H, (C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ andR¹⁸ together are ═O;

[0259] d is 1, 2 or 3;

[0260] h is 0, 1, 2, 3 or 4;

[0261] s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;

[0262] provided that at least one of s and t is 1, and the sum of m, n,p, s and t is 1-6;

[0263] provided that when p is 0 and t is 1, the sum of m, s and n is1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is1-5;

[0264] v is 0 or 1;

[0265] j and k are independently 1-5, provided that the sum of j, k andv is 1-5;

[0266] and when Q is a bond and R¹ is

[0267] Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0268] R¹⁹ and R²⁰ are independently selected from the group consistingof H, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

[0269] R²¹ is (C₁-C₆)alkyl, aryl or R²⁴-substituted aryl;

[0270] R²² is H, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹;

[0271] R²³ and R²⁴ are independently 1-3 groups independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂,—NR¹⁹R²⁰, —OH and halogeno; and

[0272] R²⁵ is H, —OH or (C₁-C₆)alkoxy.

[0273] Ar² is preferably phenyl or R¹¹-phenyl, especially(4-R¹¹)-substituted phenyl. Preferred definitions of R¹¹ are loweralkoxy, especially methoxy, and halogeno, especially fluoro.

[0274] Ar¹ is preferably phenyl or R¹⁰-substituted phenyl, especially(4-R¹⁰)-substituted phenyl. Preferably R¹⁰ is halogeno, and morepreferably fluoro.

[0275] There are several preferred definitions for the —R¹-Q-combination of variables:

[0276] Q is a bond and R¹ is lower alkylene, preferably propylene;

[0277] Q is a spiro group as defined above, wherein preferably R¹³ andR¹⁴ are each ethylene and R¹² is

[0278] and R¹ is —(CH₂)_(q) wherein q is 0-6;

[0279] Q is a bond and R¹ is

[0280] wherein the variables are chosen such that R¹ is —O—CH₂—CH(OH)—;

[0281] Q is a bond and R¹

[0282] wherein the is variables are chosen such that R¹ is—CH(OH)—(CH₂)₂—; and

[0283] Q is a bond and R¹ is

[0284] wherein the variables are chosen such that R¹ is—CH(OH)—CH₂—S(O)₀₋₂—.

[0285] A preferred compound of Formula (VIII) therefore, is one whereinG and G¹ are as defined above and in which the remaining variables havethe following definitions:

[0286] Ar¹ is phenyl or R¹⁰-substituted phenyl, wherein R¹⁰ is halogeno;

[0287] Ar² is phenyl or R¹¹-phenyl, wherein R¹¹ is 1 to 3 substituentsindependently selected from the group consisting of C₁-C₆ alkoxy andhalogeno;

[0288] Q is a bond and R¹ is lower alkylene; Q, with the 3-position ringcarbon of the azetidinone, forms the group

[0289] wherein preferably R¹³ and R¹⁴ are each ethylene and a and b areeach 1, and wherein R¹² is

[0290] Q is a bond and R¹ is —O—CH₂—CH(OH)—; Q is a bond and R¹ is—CH(OH)—(CH₂)₂—; or Q is a bond and R¹ is —CH(OH)—CH₂—S(O)₀₋₂—.

[0291] Preferred variables for G and G¹ groups of the formulae

[0292] are as follows:

[0293] R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from thegroup consisting of H, (C₁-C₆)alkyl, benzyl and acetyl.

[0294] Preferred variables for group G or G¹ of the formula:

[0295] are as follows:

[0296] R³, R^(3a), R⁴ and R^(4a) are selected from the group consistingof H, (C₁-C₆)alkyl, benzyl and acetyl;

[0297] R, R^(a) and R^(b) are independently selected from the groupconsisting of H, —OH, halogeno, —NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)alkoxyand —W—R³⁰,

[0298] wherein W is —O—C(O)— or —O—C(O)—NR³¹—, R³¹ is H and R³⁰ is(C₁-C₆)alkyl, —C(O)—(C₁-C₄)alkoxy-(C₁-C₆)alkyl, T, T-(C₁-C₆)alkyl, or T,T-(C₁-C₆)alkyl wherein T is substituted by one or two halogeno or(C₁-C₆)alkyl groups.

[0299] Preferred R³⁰ substituents are selected from the group consistingof: 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl,2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl,thiazol-2-yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl.

[0300] Preferred combinations of R, R^(a) and R^(b) are as follows:

[0301] 1) R, R^(a) and R^(b) are independently —OH or —O—C(O)—NH—R³⁰,especially wherein R^(a) is —OH and R and R^(b) are —O—C(O)—NH—R³⁰ andR³⁰ is selected from the preferred substituents identified above, orwherein R and R^(a) are each —OH and R^(b) is —O—C(O)—NH—R³⁰ wherein R³⁰is 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyl;

[0302] 2) R^(a) is —OH, halogeno, azido or (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,R^(b) is H, halogeno, azido or (C₁-C₆)alkoxy(C₁-C₆)-alkoxy, and R is—O—C(O)—NH—R³⁰, especially compounds wherein R^(a) is —OH, R^(b) is Hand R³⁰ is 2-fluorophenyl;

[0303] 3) R, R^(a) and R^(b) are independently —OH or —O—C(O)—R³⁰ andR³⁰ is (C₁-C₆)alkyl, T, or T substituted by one or two halogeno or(C₁-C₆)alkyl groups, especially compounds wherein R is —OH and R^(a) andR^(b) are —O—C(O)—R³⁰ wherein R³⁰ is 2-furyl; and

[0304] 4) R, R^(a) and R^(b) are independently —OH or halogeno. Threeadditional classes of preferred compounds are those wherein the C^(1′)anomeric oxy is beta, wherein the C^(2′) anomeric oxy is beta, andwherein the R group is alpha. G and G¹ are preferably selected from:

[0305] wherein Ac is acetyl and Ph is phenyl.

[0306] Preferably, R²⁶ is H or OH, more preferably H. The —O-Gsubstituent is preferably in the 4-position of the phenyl ring to whichit is attached.

[0307] In another embodiment, sterol and/or 5α-stanol absorptioninhibitors useful in the compositions and methods of the presentinvention are represented by Formula (IX) below:

[0308] or a pharmaceutically acceptable salt or solvate thereof, whereinin Formula (IX):

[0309] R¹ is selected from the group consisting of H, G, G¹, G², —SO₃Hand —PO₃H;

[0310] G is selected from the group consisting of: H,

[0311] (sugar derivatives)

[0312] wherein R, R^(a) and R^(b) are each independently selected fromthe group consisting of H, —OH, halo, —NH₂, azido,(C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰;

[0313] W is independently selected from the group consisting of—NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and—O—C(S)—N(R³¹)—;

[0314] R² and R⁶ are each independently selected from the groupconsisting of H, (C₁-C₆)alkyl, acetyl, aryl and aryl(C₁-C₆)alkyl;

[0315] R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are each independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, acetyl, aryl(C₁-C₆)alkyl,—C(O)(C₁-C₆)alkyl and —C(O)aryl;

[0316] R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T-(C₁-C₆)alkyl,R³²-substituted-(C₂-C₄)alkenyl, R³²-substituted-(C₁-C₆)alkyl,R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl;

[0317] R³¹ is independently selected from the group consisting of H and(C₁-C₄)alkyl;

[0318] T is independently selected from the group consisting of phenyl,furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

[0319] R³² is independently selected from 1-3 substituents which areeach independently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C_(1-C) ₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

[0320] G¹ is represented by the structure:

[0321] wherein R³³ is independently selected from the group consistingof unsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

[0322] R³⁴ is one to three substituents, each R³⁴ being independentlyselected from the group consisting of HOOC—, HS—, (CH₃)S—, H₂N—,(NH₂)(NH)C(NH)—, (NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—;

[0323] R³⁵ is independently selected from the group consisting of H andNH₂—;

[0324] R³⁶ is independently selected from the group consisting of H,unsubstituted alkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl;

[0325] G² is represented by the structure:

[0326] wherein R³⁷ and R³⁸ are each independently selected from thegroup consisting of (C₁-C₆)alkyl and aryl;

[0327] R²⁶ is one to five substituents, each R²⁶ being independentlyselected from the group consisting of:

[0328] a) H;

[0329] b) —OH;

[0330] c) —OCH₃;

[0331] d) fluorine;

[0332] e) chlorine;

[0333] f) —O-G;

[0334] g) —O-G¹;

[0335] h) —O-G²;

[0336] i) —SO₃H; and

[0337] j) —PO₃H;

[0338] provided that when R¹ is H, R²⁶ is not H, —OH, —OCH₃ or —O-G;

[0339] Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl or R¹⁰-substitutedheteroaryl;

[0340] Ar² is aryl, R¹¹-substituted aryl, heteroaryl or R¹¹-substitutedheteroaryl;

[0341] L is selected from the group consisting of:

[0342] a) a covalent bond;

[0343] b) —(CH₂)_(q)—, wherein q is 1-6;

[0344] c) —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,—NR²²— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of eand r is 1-6;

[0345] d) —(C₂-C₆)alkenylene-;

[0346] e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆cycloalkylene, f is1-5 and g is 0-5, provided that the sum of f and g is 1-6; and

[0347] f)

[0348] wherein M is —O—, —S—, —S(O)— or —S(O)₂—;

[0349] X, Y and Z are each independently selected from the groupconsisting of —CH₂—, —CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl)-;

[0350] R⁸ is selected from the group consisting of H and alkyl;

[0351] R¹⁰ and R¹¹ are each independently selected from the groupconsisting of 1-3 substituents which are each independently selectedfrom the group consisting of (C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halo;

[0352] R¹⁵ and R¹⁷ are each independently selected from the groupconsisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰;

[0353] R¹⁶ and R¹⁸are each independently selected from the groupconsisting of H, (C₁-C₆)alkyl and aryl;

[0354] or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O;

[0355] d is 1, 2 or 3;

[0356] h is 0, 1, 2, 3 or 4;

[0357] s is 0 or 1;

[0358] t is 0 or 1;

[0359] m, n and p are each independently selected from 0-4;

[0360] provided that at least one of s and t is 1, and the sum of m, n,p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, nand p is 1-5; and provided that when p is 0 and s is 1, the sum of m, tand n is 1-5;

[0361] v is 0 or 1;

[0362] j and k are each independently 1-5, provided that the sum of j, kand v is 1-5;

[0363] Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or, with the3-position ring carbon of the azetidinone, forms the spiro group

[0364] wherein R¹² is

[0365] R¹³ and R¹⁴ are each independently selected from the groupconsisting of —CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH—and —C(C₁-C₆ alkyl)=CH—; or R¹² together with an adjacent R¹³, or R¹²together with an adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)-group;

[0366] a and b are each independently 0, 1, 2 or 3, provided both arenot zero; provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, a is1; provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent;

[0367] and when Q is a bond and L is

[0368] then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl,thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl orpyridazinyl;

[0369] R¹⁹ and R²⁰ are each independently selected from the groupconsisting of H, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

[0370] R²¹ is (C₁-C₆)alkyl, aryl or R²⁴-substituted aryl;

[0371] R²² is H, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁹ or—COOR¹⁹;

[0372] R²³ and R²⁴ are each independently selected from the groupconsisting of 1-3 substituents which are each independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂,—NR¹⁹R²⁰, —OH and halo; and

[0373] R²⁵ is H, —OH or (C₁-C₆)alkoxy.

[0374] Examples of compounds of Formula (IX) which are useful in themethods and combinations of the present invention and methods for makingsuch compounds are disclosed in U.S. patent application Ser. No.10/166,942, filed Jun. 11, 2002, incorporated herein by reference. Anexample of a useful compound of this invention is one represented by theformula X:

[0375] wherein R¹ is defined as above.

[0376] A more preferred compound is one represented by formula XI:

[0377] Another useful compound is represented by Formula XII:

[0378] In another embodiment, compositions, pharmaceutical compositions,therapeutic combinations, kits and methods of treatment as describedabove are provided which comprise: (a) at least one obesity controlmedication; and (b) at least one sterol absorption inhibitor orpharmaceutically acceptable salts thereof or prodrugs thereof. Suitablesterol absorption inhibitors include substituted azetidinone compoundsor substituted β-lactam compounds such as compounds discussed above inFormulae I-XII. Other useful substituted azetidinone compounds includeN-sulfonyl-2-azetidinones such as are disclosed in U.S. Pat. No.4,983,597 and ethyl 4-(2-oxoazetidin-4-yl)phenoxy-alkanoates such as aredisclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p.1134-7, which are incorporated by reference herein.

[0379] The compounds of Formulae I-XII can be prepared by known methods,including the methods discussed above and, for example, WO 93/02048describes the preparation of compounds wherein —R¹-Q- is alkylene,alkenylene or alkylene interrupted by a hetero atom, phenylene orcycloalkylene; WO 94/17038 describes the preparation of compoundswherein Q is a spirocyclic group; WO 95/08532 describes the preparationof compounds wherein —R¹-Q- is a hydroxy-substituted alkylene group;PCT/US95/03196 describes compounds wherein —R¹-Q- is ahydroxy-substituted alkylene attached to the Ar¹ moiety through an —O—or S(O)₀₋₂— group; and U.S. Ser. No. 08/463,619, filed Jun. 5, 1995,describes the preparation of compounds wherein —R¹-Q- is ahydroxy-substituted alkylene group attached the azetidinone ring by a—S(O)₀₋₂— group.

[0380] The daily dose of the sterol absorption inhibitor(s) administeredto the subject can range from about 0.1 to about 1000 mg per day,preferably about 0.25 to about 50 mg/day, and more preferably about 10mg per day, given in a single dose or 2-4 divided doses. The exact dose,however, is determined by the attending clinician and is dependent onthe potency of the compound administered, the age, weight, condition andresponse of the patient.

[0381] For administration of pharmaceutically acceptable salts of theabove compounds, the weights indicated above refer to the weight of theacid equivalent or the base equivalent of the therapeutic compoundderived from the salt.

[0382] The compositions or therapeutic combinations of the presentinvention can further comprise at least one (one or more) activators forperoxisome proliferator-activated receptors (PPAR) which are chemicallydifferent from the obesity control medications above. These activatorsact as agonists for the peroxisome proliferator-activated receptors.Three subtypes of PPAR have been identified, and these are designated asperoxisome proliferator-activated receptor alpha (PPARα), peroxisomeproliferator-activated receptor gamma (PPARγ) and peroxisomeproliferator-activated receptor delta (PPARδ). It should be noted thatPPARδ is also referred to in the literature as PPARβ and as NUC1, andeach of these names refers to the same receptor.

[0383] PPARα regulates the metabolism of lipids. PPARα is activated byfibrates and a number of medium and long-chain fatty acids, and it isinvolved in stimulating β-oxidation of fatty acids. The PPARγ receptorsubtypes are involved in activating the program of adipocytedifferentiation and are not involved in stimulating peroxisomeproliferation in the liver. PPARδ has been identified as being useful inincreasing high density lipoprotein (HDL) levels in humans. See, e.g.,WO 97/28149.

[0384] PPARα activator compounds are useful for, among other things,lowering triglycerides, moderately lowering LDL levels and increasingHDL levels. Useful examples of PPARα activators include fibrates.

[0385] Non-limiting examples of suitable fibric acid derivatives(“fibrates”) include clofibrate (such as ethyl2-(p-chlorophenoxy)-2-methyl-propionate, for example ATROMID-S® Capsuleswhich are commercially available from Wyeth-Ayerst); gemfibrozil (suchas 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, for exampleLOPID® tablets which are commercially available from Parke Davis);ciprofibrate (C.A.S. Registry No. 52214-84-3, see U.S. Pat. No.3,948,973 which is incorporated herein by reference); bezafibrate(C.A.S. Registry No. 41859-67-0, see U.S. Pat. No. 3,781,328 which isincorporated herein by reference); clinofibrate (C.A.S. Registry No.30299-08-2, see U.S. Pat. No. 3,716,583 which is incorporated herein byreference); binifibrate (C.A.S. Registry No. 69047-39-8, see BE 884722which is incorporated herein by reference); lifibrol (C.A.S. RegistryNo. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate(2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester) which is commercially available from Abbott Laboratories orLIPANTHYL® micronized fenofibrate which is commercially available fromLabortoire Founier, France) and mixtures thereof. These compounds can beused in a variety of forms, including but not limited to acid form, saltform, racemates, enantiomers, zwitterions and tautomers.

[0386] Other examples of PPARα activators useful with the practice ofthe present invention include suitable fluorophenyl compounds asdisclosed in U.S. Pat. No. 6,028,109 which is incorporated herein byreference; certain substituted phenylpropionic compounds as disclosed inWO 00/75103 which is incorporated herein by reference; and PPARαactivator compounds as disclosed in WO 98/43081 which is incorporatedherein by reference.

[0387] Non-limiting examples of PPARγ activator include suitablederivatives of glitazones or thiazolidinediones, such as, troglitazone(such as REZULIN® troglitazone(-5-[[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione)commercially available from Parke-Davis); rosiglitazone (such asAVANDIA® rosiglitazone maleate(-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione,-2-butenedioate) commercially available from SmithKline Beecham) andpioglitazone (such as ACTOS™ pioglitazone hydrochloride(5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-]thiazolidinedionemonohydrochloride) commercially available from Takeda Pharmaceuticals).Other useful thiazolidinediones include ciglitazone, englitazone,darglitazone and BRL 49653 as disclosed in WO 98/05331 which isincorporated herein by reference; PPARγ activator compounds disclosed inWO 00/76488 which is incorporated herein by reference; and PPARγactivator compounds disclosed in U.S. Pat. No. 5,994,554 which isincorporated herein by reference.

[0388] Other useful classes of PPARγ activator compounds include certainacetylphenols as disclosed in U.S. Pat. No. 5,859,051 which isincorporated herein by reference; certain quinoline phenyl compounds asdisclosed in WO 99/20275 which is incorporated herein by reference; arylcompounds as disclosed by WO 99/38845 which is incorporated herein byreference; certain 1,4-disubstituted phenyl compounds as disclosed in WO00/63161; certain aryl compounds as disclosed in WO 01/00579 which isincorporated herein by reference; benzoic acid compounds as disclosed inWO 01/12612 & WO 01/12187 which are incorporated herein by reference;and substituted 4-hydroxy-phenylalconic acid compounds as disclosed inWO 97/31907 which is incorporated herein by reference.

[0389] PPARδ compounds are useful for, among other things, loweringtriglyceride levels or raising HDL levels. Non-limiting examples ofPPARδ activators include suitable thiazole and oxazole derivates, suchas C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which isincorporated herein by reference); certain fluoro, chloro orthio phenoxyphenylacetic acids as disclosed in WO 97/28149 which is incorporatedherein by reference; suitable non-1-oxidizable fatty acid analogues asdisclosed in U.S. Pat. No. 5,093,365 which is incorporated herein byreference; and PPARδ compounds as disclosed in WO 99/04815 which isincorporated herein by reference.

[0390] Moreover, compounds that have multiple functionality foractivating various combinations of PPARα, PPARγ and PPARδ are alsouseful with the practice of the present invention. Non-limiting examplesinclude certain substituted aryl compounds as disclosed in U.S. Pat. No.6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO00/23451; and WO 00/63153, all of which are incorporated herein byreference, are described as being useful PPARα and/or PPARγ activatorcompounds. Other non-limiting examples of useful PPARα and/or PPARγactivator compounds include activator compounds as disclosed in WO97/25042 which is incorporated herein by reference; activator compoundsas disclosed in WO 00/63190 which is incorporated herein by reference;activator compounds as disclosed in WO 01/21181 which is incorporatedherein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO01/16120 which is incorporated herein by reference; compounds asdisclosed in WO 00/63196 and WO 00/63209 which are incorporated hereinby reference; substituted 5-aryl-2,4-thiazolidinediones compounds asdisclosed in U.S. Pat. No. 6,008,237 which is incorporated herein byreference; arylthiazolidinedione and aryloxazolidinedione compounds asdisclosed in WO 00/78312 and WO 00/78313G which are incorporated hereinby reference; GW2331 or(2-(4-[difluorophenyl]-1heptylureido)ethyl]phenoxy)-2-methylbutyriccompounds as disclosed in WO 98/05331 which is incorporated herein byreference; aryl compounds as disclosed in U.S. Pat. No. 6,166,049 whichis incorporated herein by reference; oxazole compounds as disclosed inWO 01/17994 which is incorporated herein by reference; and dithiolanecompounds as disclosed in WO 01/25225 and WO 01/25226 which areincorporated herein by reference.

[0391] Other useful PPAR activator compounds include substitutedbenzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO01/14350 and WO/01/04351 which are incorporated herein by reference;mercaptocarboxylic compounds as disclosed in WO 00/50392 which isincorporated herein by reference; ascofuranone compounds as disclosed inWO 00/53563 which is incorporated herein by reference; carboxyliccompounds as disclosed in WO 99/46232 which is incorporated herein byreference; compounds as disclosed in WO 99/12534 which is incorporatedherein by reference; benzene compounds as disclosed in WO 99/15520 whichis incorporated herein by reference; o-anisamide compounds as disclosedin WO 01/21578 which is incorporated herein by reference; and PPARactivator compounds as disclosed in WO 01/40192 which is incorporatedherein by reference.

[0392] The peroxisome proliferator-activated receptor(s) activator(s)are administered in a therapeutically effective amount to treat thespecified condition, for example in a daily dose preferably ranging fromabout 50 to about 3000 mg per day, and more preferably about 50 to about2000 mg per day, given in a single dose or 2-4 divided doses. The exactdose, however, is determined by the attending clinician and is dependenton such factors as the potency of the compound administered, the age,weight, condition and response of the patient.

[0393] Also useful with the present invention are compositions ortherapeutic combinations that can further comprise one or morepharmacological or therapeutic agents or drugs such as cholesterolbiosynthesis inhibitors and/or lipid-lowering agents discussed below.

[0394] Non-limiting examples of cholesterol biosynthesis inhibitors foruse in the compositions, therapeutic combinations and methods of thepresent invention include competitive inhibitors of HMG CoA reductase,the rate-limiting step in cholesterol biosynthesis, squalene synthaseinhibitors, squalene epoxidase inhibitors and mixtures thereof.Non-limiting examples of suitable HMG CoA reductase inhibitors includestatins such as lovastatin (for example MEVACOR® which is available fromMerck & Co.), pravastatin (for example PRAVACHOL® which is availablefrom Bristol Meyers Squibb), fluvastatin, simvastatin (for exampleZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin,CI-981, rivastatin (sodium7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate)and pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoAsynthetase inhibitors, for example L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other sterol biosynthesis inhibitors such as DMP-565.Preferred HMG CoA reductase inhibitors include lovastatin, pravastatinand simvastatin. The most preferred HMG CoA reductase inhibitor issimvastatin.

[0395] Generally, a total daily dosage of cholesterol biosynthesisinhibitor(s) can range from about 0.1 to about 160 mg per day, andpreferably about 0.2 to about 80 mg/day in single or 2-3 divided doses.

[0396] The compositions, therapeutic combinations or methods of thepresent invention can further comprise one or more bile acidsequestrants. Bile acid sequestrants bind bile acids in the intestine,interrupting the enterohepatic circulation of bile acids and causing anincrease in the faecal excretion of steroids. Use of bile acidsequestrants is desirable because of their non-systemic mode of action.Bile acid sequestrants can lower intrahepatic cholesterol and promotethe synthesis of apo B/E (LDL) receptors which bind LDL from plasma tofurther reduce cholesterol levels in the blood.

[0397] Non-limiting examples of suitable bile acid sequestrants includecholestyramine (a styrene-divinylbenzene copolymer containing quaternaryammonium cationic groups capable of binding bile acids, such asQUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available fromBristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Other usefulbile acid sequestrants are disclosed in PCT Patent Applications Nos. WO97/11345 and WO 98/57652, and U.S. Pat. Nos. 3,692,895 and 5,703,188which are incorporated herein by reference. Suitable inorganiccholesterol sequestrants include bismuth salicylate plus montmorilloniteclay, aluminum hydroxide and calcium carbonate antacids.

[0398] Generally, a total daily dosage of bile acid sequestrant(s) canrange from about 1 to about 50 grams per day, and preferably about 2 toabout 16 grams per day in single or 2-4 divided doses.

[0399] The compositions or treatments of the present invention canfurther comprise one or more ileal bile acid transport (“IBAT”)inhibitors (or apical sodium co-dependent bile acid transport (“ASBT”)inhibitors) coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. The IBAT inhibitors can inhibit bile acidtransport to reduce LDL cholesterol levels. Non-limiting examples ofsuitable IBAT inhibitors include benzothiepines such as therapeuticcompounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxidestructure such as are disclosed in PCT Patent Application WO 00/38727which is incorporated herein by reference.

[0400] Generally, a total daily dosage of IBAT inhibitor(s) can rangefrom about 0.01 to about 1000 mg/day, and preferably about 0.1 to about50 mg/day in single or 2-4 divided doses.

[0401] The compositions or treatments of the present invention canfurther comprise nicotinic acid (niacin) and/or derivatives thereof. Asused herein, “nicotinic acid derivative” means a compound comprising apyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure,including acid forms, salts, esters, zwitterions and tautomers, whereavailable. Examples of nicotinic acid derivatives include niceritrol,nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide).Nicotinic acid and its derivatives inhibit hepatic production of VLDLand its metabolite LDL and increases HDL and apo A-1 levels. An exampleof a suitable nicotinic acid product is NIASPAN® (niacinextended-release tablets) which are available from Kos.

[0402] Generally, a total daily dosage of nicotinic acid or a derivativethereof can range from about 500 to about 10,000 mg/day, preferablyabout 1000 to about 8000 mg/day, and more preferably about 3000 to about6000 mg/day in single or divided doses.

[0403] The compositions or treatments of the present invention canfurther comprise one or more AcylCoA:Cholesterol O-acyltransferase(“ACAT”) Inhibitors, which can reduce LDL and VLDL levels,coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. ACAT is an enzyme responsible foresterifying excess intracellular cholesterol and may reduce thesynthesis of VLDL, which is a product of cholesterol esterification, andoverproduction of apo B-100-containing lipoproteins.

[0404] Non-limiting examples of useful ACAT inhibitors include avasimibe([[2,4,6-tris(1-methylethyl )phenyl]acetyl]sulfamic acid,2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004,lecimibide (DuP-128) and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July;60(1); 55-93, whichis incorporated by reference herein.

[0405] Generally, a total daily dosage of ACAT inhibitor(s) can rangefrom about 0.1 to about 1000 mg/day in single or 2-4 divided doses.

[0406] The compositions or treatments of the present invention canfurther comprise one or more Cholesteryl Ester Transfer Protein (“CETP”)Inhibitors coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. CETP is responsible for the exchange ortransfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

[0407] Non-limiting examples of suitable CETP inhibitors are disclosedin PCT Patent Application No. WO 00/38721 and U.S. Pat. No. 6,147,090,which are incorporated herein by reference. Pancreatic cholesteryl esterhydrolase (PCEH) inhibitors such as WAY-121898 also can becoadministered with or in combination with the peroxisomeproliferator-activated receptor(s) activator and sterol absorptioninhibitor(s) discussed above.

[0408] Generally, a total daily dosage of CETP inhibitor(s) can rangefrom about 0.01 to about 1000 mg/day, and preferably about 0.5 to about20 mg/kg body weight/day in single or divided doses.

[0409] The compositions or treatments of the present invention canfurther comprise probucol or derivatives thereof (such as AGI-1067 andother derivatives disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250),which can reduce LDL levels, coadministered with or in combination withthe peroxisome proliferator-activated receptor activator(s) and sterolabsorption inhibitor(s) discussed above.

[0410] Generally, a total daily dosage of probucol or derivativesthereof can range from about 10 to about 2000 mg/day, and preferablyabout 500 to about 1500 mg/day in single or 2-4 divided doses.

[0411] The compositions or treatments of the present invention canfurther comprise low-density lipoprotein (LDL) receptor activators,coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. Non-limiting examples of suitableLDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidinederivative that directly stimulates LDL receptor activity. See M.Huettinger et al., “Hypolipidemic activity of HOE-402 is Mediated byStimulation of the LDL Receptor Pathway”, Arterioscler. Thromb. 1993;13:1005-12.

[0412] Generally, a total daily dosage of LDL receptor activator(s) canrange from about 1 to about 1000 mg/day in single or 2-4 divided doses.

[0413] The compositions or treatments of the present invention canfurther comprise fish oil, which contains Omega 3 fatty acids (3-PUFA),which can reduce VLDL and triglyceride levels, coadministered with or incombination with the peroxisome proliferator-activated receptoractivator(s) and sterol absorption inhibitor(s) discussed above.Generally, a total daily dosage of fish oil or Omega 3 fatty acids canrange from about 1 to about 30 grams per day in single or 2-4 divideddoses.

[0414] The compositions or treatments of the present invention canfurther comprise natural water soluble fibers, such as psyllium, guar,oat and pectin, which can reduce cholesterol levels. Generally, a totaldaily dosage of natural water soluble fibers can range from about 0.1 toabout 10 grams per day in single or 2-4 divided doses.

[0415] The compositions or treatments of the present invention canfurther comprise plant sterols, plant stanols and/or fatty acid estersof plant stanols, such as sitostanol ester used in BENECOL® margarine,which can reduce cholesterol levels. Generally, a total daily dosage ofplant sterols, plant stanols and/or fatty acid esters of plant stanolscan range from about 0.5 to about 20 grams per day in single or 2-4divided doses.

[0416] The compositions or treatments of the present invention canfurther comprise antioxidants, such as probucol, tocopherol, ascorbicacid, β-carotene and selenium, or vitamins such as vitamin B₆ or vitaminB₁₂. Generally, a total daily dosage of antioxidants or vitamins canrange from about 0.05 to about 10 grams per day in single or 2-4 divideddoses.

[0417] The compositions or treatments of the present invention canfurther comprise monocyte and macrophage inhibitors such aspolyunsaturated fatty acids (PUFA), thyroid hormones including throxineanalogues such as CGS-26214 (a thyroxine compound with a fluorinatedring), gene therapy and use of recombinant proteins such as recombinantapo E. Generally, a total daily dosage of these agents can range fromabout 0.01 to about 1000 mg/day in single or 2-4 divided doses.

[0418] The present invention also provides a composition or therapeuticcombination comprising (a) at least one AcylCoA:CholesterolO-acyltransferase Inhibitor and (b) at least one substituted azetidinonecompound or substituted β-lactam compound or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.

[0419] Also useful with the present invention are compositions ortherapeutic combinations which further comprise hormone replacementagents and compositions. Useful hormone agents and compositions forhormone replacement therapy of the present invention include androgens,estrogens, progestins, their pharmaceutically acceptable salts andderivatives. Combinations of these agents and compositions are alsouseful.

[0420] The dosage of androgen and estrogen combinations vary, desirablyfrom about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mgestrogen. Examples include, but are not limited to, androgen andestrogen combinations such as the combination of esterified estrogens(sodium estrone sulfate and sodium equilin sulfate) andmethyltestosterone (17-hydroxy-17-methyl-, (17B)- androst-4-en-3-one)available from Solvay Pharmaceuticals, Inc., Marietta, Ga., under thetradename Estratest.

[0421] Estrogens and estrogen combinations may vary in dosage from about0.01 mg up to 8 mg, desirably from about 0.3 mg to about 3.0 mg.Examples of useful estrogens and estrogen combinations include:

[0422] (a) the blend of nine (9) synthetic estrogenic substancesincluding sodium estrone sulfate, sodium equilin sulfate, sodium 17α-dihydroequilin sulfate, sodium 17 α-estradiol sulfate, sodium 17β-dihydroequilin sulfate, sodium 17 α-dihydroequilenin sulfate, sodium17 β-dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17β-estradiol sulfate; available from Duramed Pharmaceuticals, Inc.,Cincinnati, Ohio, under the tradename Cenestin;

[0423] (b) ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol; available by Schering PloughCorporation, Kenilworth, N.J., under the tradename Estinyl;

[0424] (c) esterified estrogen combinations such as sodium estronesulfate and sodium equilin sulfate; available from Solvay under thetradename Estratab and from Monarch Pharmaceuticals, Bristol, Tenn.,under the tradename Menest;

[0425] (d) estropipate (piperazine estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-estrone sulfate); available from Pharmacia & Upjohn,Peapack, N.J., under the tradename Ogen and from Women First HealthCare, Inc., San Diego, Calif., under the tradename Ortho-Est; and

[0426] (e) conjugated estrogens (17 α-dihydroequilin, 17 α-estradiol,and 17 β-dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals,Philadelphia, Pa., under the tradename Premarin.

[0427] Progestins and estrogens may also be administered with a varietyof dosages, generally from about 0.05 to about 2.0 mg progestin andabout 0.001 mg to about 2 mg estrogen, desirably from about 0.1 mg toabout 1 mg progestin and about 0.01 mg to about 0.5 mg estrogen.Examples of progestin and estrogen combinations that may vary in dosageand regimen include:

[0428] (a) the combination of estradiol (estra-1, 3, 5 (10)-triene-3, 17β-diol hemihydrate) and norethindrone (17 β-acetoxy-19-nor-17α-pregn-4-en-20-yn-3-one); which is available from Pharmacia & Upjohn,Peapack, N.J., under the tradename Activella;

[0429] (b) the combination of levonorgestrel (d(−)-13 β-ethyl-17α-ethinyl-17 β-hydroxygon-4-en-3-one) and ethinyl estradial; availablefrom Wyeth-Ayerst under the tradename Alesse, from Watson Laboratories,Inc., Corona, Calif., under the tradenames Levora and Trivora, MonarchPharmaceuticals, under the tradename Nordette, and from Wyeth-Ayerstunder the tradename Triphasil;

[0430] (c) the combination of ethynodiol diacetate (19-nor-17α-pregn-4-en-20-yne-3 β, 17-diol diacetate) and ethinyl estradiol;available from G. D. Searle & Co., Chicago, Ill., under the tradenameDemulen and from Watson under the tradename Zovia;

[0431] (d) the combination of desogestrel(13-ethyl-11-methylene-18,19-dinor-17 α-pregn-4-en-20-yn-17-ol) andethinyl estradiol; available from Organon under the tradenames Desogenand Mircette, and from Ortho-McNeil Pharmaceutical, Raritan, N.J., underthe tradename Ortho-Cept;

[0432] (e) the combination of norethindrone and ethinyl estradiol;available from Parke-Davis, Morris Plains, N.J., under the tradenamesEstrostep and femhrt, from Watson under the tradenames Microgestin,Necon, and Tri-Norinyl, from Ortho-McNeil under the tradenames Modiconand Ortho-Novum, and from Warner Chilcott Laboratories, Rockaway, N.J.,under the tradename Ovcon;

[0433] (f) the combination of norgestrel ((±)-13-ethyl-17-hydroxy-18,19-dinor-17 α-preg-4-en-20-yn-3-one) and ethinyl estradiol; availablefrom Wyeth-Ayerst under the tradenames Ovral and Lo/Ovral, and fromWatson under the tradenames Ogestrel and Low-Ogestrel;

[0434] (g) the combination of norethindrone, ethinyl estradiol, andmestranol (3-methoxy-19-nor-17 α-pregna-1,3,5(10)-trien-20-yn-17-ol);available from Watson under the tradenames Brevicon and Norinyl;

[0435] (h) the combination of 17 β-estradiol(estra-1,3,5(10)-triene-3,17 β-diol) and micronized norgestimate (17α-17-(Acetyloxyl)-13-ethyl-1 8,19-dinorpregn-4-en-20-yn-3-one3-oxime);available from Ortho-McNeil under the tradename Ortho-Prefest;

[0436] (i) the combination of norgestimate(18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17(α)-(+)-) and ethinyl estradiol; available from Ortho-McNeil underthe tradenames Ortho Cyclen and Ortho Tri-Cyclen; and

[0437] j) the combination of conjugated estrogens (sodium estronesulfate and sodium equilin sulfate) and medroxyprogesterone acetate(20-dione, 17-(acetyloxy)-6-methyl-, (6(α))- pregn-4-ene-3); availablefrom Wyeth-Ayerst under the tradenames Premphase and Prempro.

[0438] In general, a dosage of progestins may vary from about 0.05 mg toabout 10 mg or up to about 200 mg if microsized progesterone isadministered. Examples of progestins include norethindrone; availablefrom ESI Lederle, Inc., Philadelphia, Pa., under the tradename Aygestin,from Ortho-McNeil under the tradename Micronor, and from Watson underthe tradename Nor-QD; norgestrel; available from Wyeth-Ayerst under thetradename Ovrette; micronized progesterone (pregn-4-ene-3, 20-dione);available from Solvay under the tradename Prometrium; andmedroxyprogesterone acetate; available from Pharmacia & Upjohn under thetradename Provera.

[0439] The compositions, therapeutic combinations or methods of thepresent invention can further comprise one or more blood modifiers.Useful blood modifiers include but are not limited to anti-coagulants(argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol,lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium,warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin,cilostazol, dalteparin sodium, danaparoid sodium, dazoxibenhydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen,ifetroban, ifetroban sodium, lamifiban, lotrafiban hydrochloride,napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban,tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogenreceptor antagonists (roxifiban acetate, fradafiban, orbofiban,lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrelbisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride,aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate,droxicam, diclofenac, sulfinpyrazone, piroxicam, dipyridamole); plateletaggregation inhibitors (acadesine, beraprost, beraprost sodium,ciprostene calcium, itazigrel, lifarizine, lotrafiban hydrochloride,orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban.xemilofiban); hemorrheologic agents (pentoxifylline); lipoproteinassociated coagulation inhibitor; Factor VIIa inhibitors(4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-4-thiones,quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4-ones,imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides,naphthalene-2-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl}amidetrifluoroacetate, dibenzofuran-2-sulfonic acid{1-[3-(aminomethyl)-benzyl]-5-oxo-pyrrolidin-3-yl}-amide,tolulene-4-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate, 3,4-dihydro-1H-isoquinoline-2-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl}-amidetrifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines,disubstituted triazolines, substitutedn-[(aminoiminomethyl)phenyl]propylamides, substitutedn-[(aminomethyl)phenyl]propylamides, tissue factor pathway inhibitor(TFPI), low molecular weight heparins, heparinoids, benzimidazolines,benzoxazolinones, benzopiperazinones, indanones, dibasic (amidinoaryl)propanoic acid derivatives, amidinophenyl-pyrrolidines,amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles,amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidicFactor Xa inhibitors).

[0440] The compositions, therapeutic combinations or methods of thepresent invention can further comprise one or more cardiovascular agentsdifferent from the sterol absorption inhibitors discussed above. Usefulcardiovascular agents include but are not limited to calcium channelblockers (clentiazem maleate, amlodipine besylate, isradipine,nimodipine, felodipine, nilvadipine, nifedipine, teludipinehydrochloride, diltiazem hydrochloride, belfosdil, verapamilhydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride,labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol,acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunololhydrochloride, carteolol hydrochloride, celiprolol hydrochloride,cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranololhydrochloride, diacetolol hydrochloride, dilevalol hydrochloride,esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate,labetalol hydrochloride, levobetaxolol hydrochloride, levobunololhydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate,nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranololhydrochloride, sotalol hydrochloride, timolol, timolol maleate,tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate,nebivolol); adrenergic stimulants; angiotensin converting enzyme (ACE)inhibitors (benazepril hydrochloride, benazeprilat, captopril, delaprilhydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride,pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril,spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate,lisinopril, zofenopril calcium, perindopril erbumine); antihypertensiveagents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazidesodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride,dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,guanfacine hydrochloride, methyidopa, metoprolol succinate, moexiprilhydrochloride, monatepil maleate, pelanserin hydrochloride,phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol,quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride,candesartan, candesartan cilexetil, telmisartan, amlodipine besylate,amlodipine maleate, bevantolol hydrochloride); angiotensin II receptorantagonists (candesartan, irbesartan, losartan potassium, candesartancilexetil, telmisartan); anti-anginal agents (amlodipine besylate,amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride,butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprololsuccinate, molsidomine, monatepil maleate, primidolol, ranolazinehydrochoride, tosifen, verapamil hydrochloride); coronary vasodilators(fostedil, azaclorzine hydrochloride, chromonar hydrochloride,clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine,erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate,lidoflazine, mioflazine hydrochloride, mixidine, molsidomine,nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenololhydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatylnitrate, terodiline hydrochloride, tolamolol, verapamil); diuretics (thecombination product of hydrochlorothiazide and spironolactone and thecombination product of hydrochlorothiazide and triamterene).

[0441] The compositions, therapeutic combinations or methods of thepresent invention can further comprise one or more antidiabeticmedications for reducing blood glucose levels in a human. Usefulantidiabetic medications include, but are not limited to, drugs thatreduce energy intake or suppress appetite, drugs that increase energyexpenditure and nutrient-partitioning agents. Suitable antidiabeticmedications include, but are not limited to, sulfonylurea (such asacetohexamide, chlorpropamide, gliamilide, gliclazide, glimepiride,glipizide, glyburide, glibenclamide, tolazamide, and tolbutamide),meglitinide (such as repaglinide and nateglinide), biguanide (such asmetformin and buformin), thiazolidinedione (such as troglitazone,rosiglitazone, pioglitazone, ciglitazone, englitazone, anddarglitazone), alpha-glucosidase inhibitor (such as acarbose, miglitol,camiglibose, and voglibose), certain peptides (such as amlintide,pramlintide, exendin, and GLP-1 agonistic peptides), and orallyadministrable insulin or insulin composition for intestinal deliverythereof. Generally, a total dosage of the above-described antidiabeticmedications can range from 0.1 to 1,000 mg/day in single or 2-4 divideddoses.

[0442] Mixtures of any of the pharmacological or therapeutic agentsdescribed above can be used in the compositions and therapeuticcombinations of these other embodiments of the present invention.

[0443] In another embodiment, a method of treating or preventing obesityis provided comprising the step of administering to a subject in need ofsuch treatment an effective amount of a composition comprising at leastone sterol absorption inhibitor and/or at least one 5α-stanol absorptioninhibitor.

[0444] In another embodiment, a method of treating or preventing obesityis provided comprising the step of administering to a subject in need ofsuch treatment an effective amount of a composition comprising at leastone sterol and/or 5α-stanol absorption inhibitor represented by Formula(II) below:

[0445] The compositions and therapeutic combinations of the presentinvention can be administered to a subject in need of such treatment ina therapeutically effective amount to treat vascular conditions and/orobesity. The compositions and treatments can be administered by anysuitable means that produce contact of these compounds with the site ofaction in the body, for example in the plasma, liver or small intestineof a subject.

[0446] The daily dosage for the various compositions and therapeuticcombinations described above can be administered to a subject in asingle dose or in multiple subdoses, as desired. Subdoses can beadministered 2 to 6 times per day, for example. Sustained releasedosages can be used. Where the obesity control medication(s) and sterolabsorption inhibitor(s) are administered in separate dosages, the numberof doses of each component given per day may not necessarily be thesame, e.g., one component may have a greater duration of activity andwill therefore need to be administered less frequently.

[0447] The compositions, therapeutic combinations or medicaments of thepresent invention can further comprise one or more pharmaceuticallyacceptable carriers, one or more excipients and/or one or moreadditives. The pharmaceutical compositions can comprise about 1 to about99 weight percent of active ingredient (one or more compounds of FormulaI-XII), and preferably about 5 to about 95 percent active ingredient.

[0448] Useful pharmaceutically acceptable carriers can be either solid,liquid or gas. Non-limiting examples of pharmaceutically acceptablecarriers include solids and/or liquids such as magnesium carbonate,magnesium stearate, talc, sugar, lactose, ethanol, glycerol, water andthe like. The amount of carrier in the treatment composition ortherapeutic combination can range from about 5 to about 99 weightpercent of the total weight of the treatment composition or therapeuticcombination. Non-limiting examples of suitable pharmaceuticallyacceptable excipients and additives include non-toxic compatiblefillers, binders such as starch, polyvinyl pyrrolidone or celluloseethers, disintegrants such as sodium starch glycolate, crosslinkedpolyvinyl pyrrolidone or croscarmellose sodium, buffers, preservatives,anti-oxidants, lubricants, flavorings, thickeners, coloring agents,wetting agents such as sodium lauryl sulfate, emulsifiers and the like.The amount of excipient or additive can range from about 0.1 to about 95weight percent of the total weight of the treatment composition ortherapeutic combination. One skilled in the art would understand thatthe amount of carrier(s), excipients and additives (if present) canvary. Further examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions can be found in A.Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20^(th)Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.

[0449] Useful solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. An example ofa preparation of a preferred solid form dosage formulation is providedbelow.

[0450] Useful liquid form preparations include solutions, suspensionsand emulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0451] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0452] Also useful are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0453] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0454] Preferably the compound is administered orally.

[0455] In another embodiment, the present invention provides the use ofat least one compound represented by Formulae (I-XII) for manufacture ofa medicament (such as one of the compositions discussed above) for thetreatment of obesity.

[0456] The following formulation exemplifies one of the dosage forms ofthis invention. In the formulation, the term “Active Compound I”designates a sterol or 5α-stanol absorption inhibitor such as any of thecompounds of Formulas I-XII described herein above and the term “ActiveCompound II” designates an obesity control medication described hereinabove.

EXAMPLE

[0457] Tablets No. Ingredient mg/tablet 1 Active Compound I 10 2 Lactosemonohydrate NF 55 3 Microcrystalline cellulose NF 20 4 Povidone USP(K29-32) 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate NF 2 7Magnesium stearate NF 1 Total 100

[0458] In the present invention, the above-described tablet can becoadministered with a tablet, capsule, etc. comprising a dosage ofActive Compound II, for example an obesity control medication asdescribed above.

[0459] Method of Manufacture

[0460] Mix Item No. 4 with purified water in suitable mixer to formbinder solution. Spray the binder solution and then water over Items 1,2 and 6 and a portion of item 5 in a fluidized bed processor togranulate the ingredients. Continue fluidization to dry the dampgranules. Screen the dried granule and blend with Item No. 3 and theremainder of Item No. 5. Add Item No. 7 and mix. Compress the mixture toappropriate size and weight on a suitable tablet machine.

[0461] For coadministration in separate tablets or capsules,representative formulations comprising a sterol or 5α-stanol absorptioninhibitor such as are discussed above are well known in the art andrepresentative formulations comprising an obesity control medicationsuch as are discussed above are well known in the art. It iscontemplated that where the two active ingredients are administered as asingle composition, the dosage forms disclosed above for sterol or5α-stanol absorption inhibitor may readily be modified using theknowledge of one skilled in the art.

[0462] Since the present invention relates to controlling obesity and/orreducing the plasma sterol (especially cholesterol) or 5α-stanolconcentrations or levels by treatment with a combination of activeingredients wherein the active ingredients may be administeredseparately, the invention also relates to combining separatepharmaceutical compositions in kit form. That is, a kit is contemplatedwherein two separate units are combined: a pharmaceutical compositioncomprising at least one obesity control medication and a separatepharmaceutical composition comprising at least one sterol absorptioninhibitor as described above. The kit will preferably include directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components must beadministered in different dosage forms (e.g., oral and parenteral) orare administered at different dosage intervals.

[0463] The treatment compositions and therapeutic combinations of thepresent invention can inhibit the intestinal absorption of cholesterolin subjects and can be useful in the treatment and/or prevention ofvascular conditions, such as vascular inflammation, atherosclerosis,hypercholesterolemia and sitosterolemia, stroke, obesity and lowering ofplasma levels of cholesterol in subjects, in particular in humans.

[0464] In another embodiment of the present invention, the compositionsand therapeutic combinations of the present invention can reduce plasmaconcentration of at least one sterol selected from the group consistingof cholesterol and phytosterols (such as sitosterol, campesterol,stigmasterol and avenosterol), or 5α-stanols (such as cholestanol,5α-campestanol, 5α-sitostanol), and mixtures thereof. The plasmaconcentration can be reduced by administering to a subject in need ofsuch treatment an effective amount of at least one treatment compositioncomprising at least one sterol and/or 5α-stanol absorption inhibitordescribed above or a treatment composition or therapeutic combinationcomprising at least one obesity control medication and at least onesterol and/or 5α-stanol absorption inhibitor described above. Thereduction in plasma concentration of sterols can range from about 1 toabout 70 percent, and preferably about 10 to about 50 percent. Methodsof measuring serum total blood cholesterol and total LDL cholesterol arewell known to those skilled in the art and for example include thosedisclosed in PCT WO 99/38498 at page 11, incorporated by referenceherein. Methods of determining levels of other sterols in serum aredisclosed in H. Gylling et al., “Serum Sterols During Stanol EsterFeeding in a Mildly Hypercholesterolemic Population”, J. Lipid Res. 40:593-600 (1999), incorporated by reference herein.

[0465] Illustrating the preparation of a compound of Formula II is thefollowing example which, however, is not to be considered as limitingthe invention to their details. Unless otherwise indicated, all partsand percentages in the following examples, as well as throughout thespecification, are by weight.

EXAMPLE Preparation of Compound of Formula (II)

[0466] Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g,0.25 mol) in CH₂Cl₂ (200 ml), was added 4-dimethylaminopyridine (2.5 g,0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and the reaction mixturewas cooled to 0° C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) wasadded as a solution in CH₂Cl₂ (375 ml) dropwise over 1 h, and thereaction was allowed to warm to 22° C. After 17 h, water and H₂SO₄ (2N,100 ml), was added the layers were separated, and the organic layer waswashed sequentially with NaOH (10%), NaCl (sat'd) and water. The organiclayer was dried over MgSO₄ and concentrated to obtain a semicrystallineproduct.

[0467] Step 2): To a solution of TiCl₄ (18.2 ml, 0.165 mol) in CH₂Cl₂(600 ml) at 0° C., was added titanium isopropoxide (16.5 ml, 0.055 mol).After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as asolution in CH₂Cl₂ (100 ml). After 5 min., diisopropylethylamine (DIPEA)(65.2 ml, 0.37 mol) was added and the reaction mixture was stirred at 0°C. for 1 h, the reaction mixture was cooled to −20° C., and4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added asa solid. The reaction mixture was stirred vigorously for 4 h at −20° C.,then acetic acid was added as a solution in CH₂Cl₂ dropwise over 15 min,the reaction mixture was allowed to warm to 0° C., and H₂SO₄ (2N) wasadded. The reaction mixture was stirred an additional 1 h, the layerswere separated, washed with water, separated and the organic layer wasdried. The crude product was crystallized from ethanol/water to obtainthe pure intermediate.

[0468] Step 3): To a solution of the product of Step 2 (8.9 g, 14.9mmol) in toluene (100 ml) at 50° C., was addedN,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After 0.5h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixturestirred at 50° C. for an additional 3 h. The reaction mixture was cooledto 22° C., CH₃OH (10 ml), was added. The reaction mixture was washedwith HCl (1N), NaHCO₃ (1N) and NaCl (sat'd.), and the organic layer wasdried over MgSO₄.

[0469] Step 4): To a solution of the product of Step 3 (0.94 g, 2.2mmol) in CH₃OH (3 ml), was added water (1 ml) and LiOH.H₂O (102 mg, 2.4mmole). The reaction mixture was stirred at 22° C. for 1 h and thenadditional LiOH.H₂O (54 mg, 1.3 mmole) was added. After a total of 2 h,HCl (1N) and EtOAc was added, the layers were separated, the organiclayer was dried and concentrated in vacuo. To a solution of theresultant product (0.91 g, 2.2 mmol) in CH₂Cl₂ at 22° C., was addedClCOCOCl (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. Thesolvent was removed in vacuo.

[0470] Step 5): To an efficiently stirred suspension of4-fluorophenylzinc chloride (4.4 mmol) prepared from4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl₂(0.6 g, 4.4 mmol) at 4° C., was addedtetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed bythe product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml).The reaction was stirred for 1 h at 0° C. and then for 0.5 h at 22° C.HCl (1N, 5 ml) was added and the mixture was extracted with EtOAc. Theorganic layer was concentrated to an oil and purified by silica gelchromatography to obtain1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone:

[0471] HRMS calc'd for C₂₄H₁₉F₂NO₃=408.1429, found 408.1411.

[0472] Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3ml), was added(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole(120 mg, 0.43 mmol) and the mixture was cooled to −20° C. After 5 min,borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) wasadded dropwise over 0.5 h. After a total of 1.5 h , CH₃OH was addedfollowed by HCl (1N) and the reaction mixture was extracted with EtOActo obtain1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone(compound 6A-1) as an oil. ¹H in CDCl₃ d H3=4.68. J=2.3 Hz. Cl (M⁺H)500.

[0473] Use of(S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborolegives the corresponding 3(R)-hydroxypropyl azetidinone (compound 6B-1).¹H in CDCl₃ d H3=4.69. J=2.3 Hz. Cl (M⁺H) 500.

[0474] To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2ml), was added 10% Pd/C (0.03 g) and the reaction mixture was stirredunder a pressure (60 psi) of H₂ gas for 16 h. The reaction mixture wasfiltered and the solvent was concentrated to obtain compound 6A. Mp164-166° C.; Cl (M⁺H) 410. [α]_(D) ²⁵=−28.1° (c 3, CH₃OH). Elementalanalysis calc'd for C₂₄H₂₁F₂NO₃: C 70.41; H 5.17; N 3.42; found C 70.25;H 5.19; N 3.54.

[0475] Similarly treat compound 6B-1 to obtain compound 6B.

[0476] Mp 129.5-132.5° C.; Cl (M⁺H) 410. Elemental analysis calc'd forC₂₄H₂₁ F₂NO₃: C 70.41; H 5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

[0477] Step 6′ (Alternative): To a solution of the product of Step 5(0.14 g, 0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) andthe reaction was stirred under a pressure (60 psi) of H₂ gas for 16 h.The reaction mixture was filtered and the solvent was concentrated toafford a 1:1 mixture of compounds 6A and 6B.

[0478] It will be appreciated by those skilled in the art that changescould be made to the embodiments described above without departing fromthe broad inventive concept thereof. It is understood, therefore, thatthis invention is not limited to the particular embodiments disclosed,but it is intended to cover modifications that are within the spirit andscope of the invention, as defined by the appended claims.

Therefore, we claim:
 1. A composition comprising: (a) at least oneobesity control medication; and (b) at least one sterol absorptioninhibitor or at least one 5α-stanol absorption inhibitor or apharmaceutically acceptable salt thereof or a solvate thereof.
 2. Thecomposition according to claim 1, wherein the at least one sterol or5α-stanol absorption inhibitor is represented by Formula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: Ar¹ and Ar² are independently selected from the groupconsisting of aryl and R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X, Y and Z are independently selected from thegroup consisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; Rand R² are independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷; R¹ and R³ are independentlyselected from the group consisting of hydrogen, lower alkyl and aryl; qis 0 or 1; r is 0 or 1; m, n and p are independently selected from 0, 1,2, 3 or 4; provided that at least one of q and r is 1, and the sum of m,n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and ris 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituentsindependently selected from the group consisting of lower alkyl, —OR ,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(loweralkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN, —NO₂ and halogen; R⁵ is 1-5substituents independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(loweralkylene)COOR⁶ and —CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen, lower alkyl, aryl andaryl-substituted lower alkyl; and R⁹ is lower alkyl, aryl oraryl-substituted lower alkyl.
 3. The composition according to claim 2,wherein the sterol or 5α-stanol absorption inhibitor is represented byFormula (II) below:


4. The composition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (III):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above: Ar¹ is R³-substituted aryl; Ar² isR⁴-substituted aryl; Ar³ is R⁵-substituted aryl; Y and Z areindependently selected from the group consisting of —CH₂—, —CH(loweralkyl)- and —C(dilower alkyl)-; A is selected from —O—, —S—, —S(O)— or—S(O)₂—; R¹ is selected from the group consisting of —OR, —O(CO)R,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O; q is 1, 2or 3; p is 0, 1, 2, 3 or 4; R⁵ is 1-3 substituents independentlyselected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl, —NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-loweralkyl, -(lower alkylene)-COOR⁶, and —CH═CH—COOR⁶; R³ and R⁴ areindependently 1-3 substituents independently selected from the groupconsisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃ andp-halogeno; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl. 5.The composition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above: A is selected from the group consistingof R²-substituted heterocycloalkyl, R²-substituted heteroaryl,R²-substituted benzofused heterocycloalkyl, and R²-substitutedbenzofused heteroaryl; Ar¹ is aryl or R³-substituted aryl; Ar² is arylor R⁴-substituted aryl; Q is a bond or, with the 3-position ring carbonof the azetidinone, forms the spiro group

R¹ is selected from the group consisting of: —(CH₂)_(q)—, wherein q is2-6, provided that when Q forms a spiro ring, q can also be zero or 1;—(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene, —NR⁸— or—S(O)₀₋₂, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆ alkenylene)-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆)alkyl), —CH═CH— and —C(C₁-C₆ alkyl)=CH—;or R⁵ together with an adjacent R⁶, or R⁵ together with an adjacent R⁷,form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and b are independently0, 1, 2 or 3, provided both are not zero; provided that when R⁶ is—CH═CH— or —C(C₁-C₆ alkyl)=CH—, a is 1; provided that when R⁷ is —CH═CH—or —C(C₁-C₆ alkyl)=CH—, b is 1; provided that when a is 2 or 3, the R⁶'scan be the same or different; and provided that when b is 2 or 3, theR⁷'s can be the same or different; and when Q is a bond, R¹ also can beselected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independentlyselected from the group consisting of —CH₂—, —CH(C₁-C₆ alkyl)- and—C(di-(C₁-C₆) alkyl); R¹⁰ and R¹² are independently selected from thegroup consisting of —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵; R¹¹and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or1; t is 0 or 1; m, n and p are independently 0-4; provided that at leastone of s and t is 1, and the sum of m, n, p, s and t is 1-6; providedthat when p is 0 and t is 1, the sum of m, s and n is 1-5; and providedthat when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1;j and k are independently 1-5, provided that the sum of j, k and v is1-5; R² is 1-3 substituents on the ring carbon atoms selected from thegroup consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substitutedaryl, R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆ alkylene)-, NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-, —NHC(O)R¹⁶, OH C₁-C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

is where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆)alkoxy, aryloxy,(C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—; R³ and R⁴ are independentlyselected from the group consisting of 1-3 substituents independentlyselected from the group consisting of (C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴,—O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴, —O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵,—NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹, —NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵,—COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶, —O(CH₂)₁₋₁₀—COOR¹⁴,—O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴, —CH═CH—COOR¹⁴, —CF₃,—CN, —NO₂ and halogen; R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl,—C(O)R¹⁴ or —COOR¹⁴; R⁹ and R¹⁷ are independently 1-3 groupsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno; R¹⁴and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R¹⁶ is(C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl; R¹⁸ is hydrogen or(C₁-C₆)alkyl; and R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy.
 6. Thecomposition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above: Ar¹ is aryl, R¹⁰-substituted aryl orheteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X and Y are independently selected from the groupconsisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R is—OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, lower alkyl oraryl; or R and R¹ together are ═O; q is 0 or 1; r is 0, 1 or 2; m and nare independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n andq is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituents independently selected fromthe group consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁵ is 1-5 substituents independently selected from thegroup consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R¹⁰is 1-5 substituents independently selected from the group consisting oflower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen.
 7. The compositionaccording to claim 1, where the at least one sterol absorption inhibitoris represented by Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(loweralkyl)=CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)- group; u and v areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R₂ is —CH═CH— or —C(lower alkyl)=CH—, v is 1; provided that when R₃is —CH═CH— or —C(lower alkyl)=CH—, u is 1; provided that when v is 2 or3, the R₂'s can be the same or different; and provided that when u is 2or 3, the R₃'s can be the same or different; R₄ is selected fromB—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5; B—(CH₂)_(q)—, whereinq is 0, 1, 2, 3, 4, 5 or 6; B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—,—C(O)—, phenylene, —N(R₈)—or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and r is0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5or 6; B—(C₂-C₆ alkenylene)-; B—(C₄-C₆ alkadienylene)-;B—(CH₂)_(t)-Z-(C₂-C₆ alkenylene)-, wherein Z is as defined above, andwherein t is 0, 1, 2 or 3, provided that the sum of t and the number ofcarbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B—(CH₂)_(f) 13V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is 1, 2, 3, 4 or 5 andg is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4,5 or 6; B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B—(C₂-C₆alkenylene)-V—(CH₂)_(t)—, wherein V and t are as defined above, providedthat the sum of t and the number of carbon atoms in the alkenylene chainis 2, 3, 4, 5 or 6; B—(CH₂)_(a)-Z-(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z andV are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; orT-(CH₂)_(s)—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1,2, 3, 4, 5 or 6; or R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted beteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂, —N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-,N(R₈)(R₉)-lower alkylenyloxy-,—S(O)₂NH₂ and 2-(trimethylsilyl )-ethoxymethyl; R₇ is 1-3 groupsindependently selected from the group consisting of lower alkyl, loweralkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno; R₈ and R₉ areindependently selected from H or lower alkyl; R₁₀ is selected from loweralkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl; R₁₁ is selected from OH,lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl; R₁₂ is selectedfrom H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl; R₁₃ is selected from —O—,—CH₂—, —NH—, —N(lower alkyl)— or —NC(O)R₁₉; R₁₅, R₁₆ and R₁₇ areindependently selected from the group consisting of H and the groupsdefined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇, together withadjacent carbon atoms to which they are attached, form a dioxolanylring; R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and R₂₀ andR₂₁ are independently selected from the group consisting of phenyl,W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above.
 8. Thecomposition according to claim 1, wherein the at least one sterolabsorption inhibitor is represented by Formula (VIIA) or (VIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein: A is—CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2; B is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4; E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds; R is hydrogen, C₁-C₁₅ alkyl, straight or branched,saturated or containing one or more double bonds, or B—(CH₂)_(r)—,wherein r is 0, 1, 2, or 3; R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′) areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino,dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂; R₄ is

wherein n is 0, 1, 2 or 3; R₅ is lower alkyl; and R₆ is OH, lower alkyl,phenyl, benzyl or substituted phenyl wherein the substituents are 1-3groups independently selected from the group consisting of lower alkyl,lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino anddilower alkylamino.
 9. The composition according to claim 1, wherein theat least one sterol absorption inhibitor is represented by Formula(VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above, R²⁶ is H or OG¹; G and G¹ areindependently selected from the group consisting of

provided that when R²⁶ is H or OH, G is not H; R, R^(a) and R^(b) areindependently selected from the group consisting of H, —OH, halogeno,—NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy or —W—R³⁰; W is independentlyselected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ is selected fromthe group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is selected from thegroup consisting of H and (C₁-C₄)alkyl; T is selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,imidazolyl and pyridyl; R³² is independently selected from 1-3substituents independently selected from the group consisting ofhalogeno, (C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy,methylenedioxy, oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, —N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl,—C(O)—N((C₁-C₄)alkyl)₂, —C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or a(C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl orR¹⁰-substituted aryl; Ar² is aryl or R¹¹-substituted aryl; Q is a bondor, with the 3-position ring carbon of the azetidinone, forms the spirogroup

R¹ is selected from the group consisting of —(CH₂)_(q)—, wherein q is2-6, provided that when Q forms a spiro ring, q can also be zero or 1;—(CH₂)_(e)-E-(CH₂)_(r), wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆)alkenylene-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided thatwhen R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when ais 2 or 3, the R¹³'s can be the same or different; and provided thatwhen b is 2 or 3, the R¹⁴'s can be the same or different; and when Q isa bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independently selectedfrom the group consisting of —CH₂—, —CH(C₁-C₆)alkyl- and—C(di-(C₁-C₆)alkyl); R¹⁰ and R¹¹ are independently selected from thegroup consisting of 1-3 substituents independently selected from thegroup consisting of (C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)—COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen; R¹⁵ andR¹⁷ are independently selected from the group consisting of —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰; R¹⁶ and R¹⁸ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl and aryl; or R¹⁵and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O; d is 1, 2 or 3;h is 0, 1, 2, 3 or 4; S is 0 or 1; t is 0 or 1; m, n and p areindependently 0-4; provided that at least one of s and t is 1, and thesum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1,the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1,the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently1-5, provided that the sum of j, k and v is 1-5; and when Q is a bondand R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are independently selected from the group, consisting of H,(C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are independently 1-3groups independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halogeno; andR²⁵ is H, —OH or (C₁-C₆)alkoxy.
 10. The composition according to claim1, wherein the at least one sterol absorption inhibitor is representedby Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX): R¹ is selected from the group consisting of H, G, G¹, G²,—SO₃H and —PO₃H; G is selected from the group consisting of: H,

wherein R, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, halo, —NH₂, azido,(C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰; W is independently selected fromthe group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—,—NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ are each independentlyselected from the group consisting of H, (C₁-C₆)alkyl, acetyl, aryl andaryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,acetyl, aryl(C₁-C₆)alkyl, -C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ isindependently selected from the group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is independentlyselected from the group consisting of H and (C₁-C₄)alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² isindependently selected from 1-3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G¹ isrepresented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HS—, (CH₃)S—, H₂N—, (NH₂)(NH)C(NH)—,(NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—;. R³⁵ is independently selected fromthe group consisting of H and NH₂—; R³⁶ is independently selected fromthe group consisting of H, unsubstituted alkyl, R³⁴-substituted alkyl,unsubstituted cycloalkyl and R³⁴-substituted cycloalkyl; G² isrepresented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁-C₆)alkyl and aryl; R²⁶ is one to five substituents,each R²⁶ being independently selected from the group consisting of: a)H; b) —OH; c) —OCH₃; d) fluorine; e) chlorine; f) —O-G; g) —O-G¹; h)—O-G²; i) —SO₃H; and j) —PO₃H; provided that when R¹ is H, R²⁶ is not H,—OH, —OCH₃ or —O-G; Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl orR¹⁰-substituted heteroaryl; Ar² is aryl, R¹¹-substituted aryl,heteroaryl or R¹¹-substituted heteroaryl; L is selected from the groupconsisting of: a) a covalent bond; b) —(CH₂)_(q)—, wherein q is 1-6; c)—(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; d) —(C₂-C₆)alkenylene-; e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; and f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are eachindependently selected from the group consisting of —CH₂—,—CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl)-; R⁸ is selected from the groupconsisting of H and alkyl; R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of (C₁-C₆)alkyl, —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰,—NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹,—CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN,—NO₂ and halo; R¹⁵ and R¹⁷ are each independently selected from thegroup consisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰; R¹⁶ andR¹⁸are each independently selected from the group consisting of H,(C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is0 or 1; m, n and p are each independently selected from 0-4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;v is 0 or 1; j and k are each independently 1-5, provided that the sumof j, k and v is 1-5; Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or,with the 3-position ring carbon of the azetidinone, forms the spirogroup

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent; and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are each independentlyselected from the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halo; and R²⁵ is H, —OH or(C₁-C₆)alkoxy.
 11. The composition according to claim 1, wherein the atleast one obesity medication is selected from the group consisting ofnoradrenergic agents, serotonergic agents, thermogenic agents andcombinations thereof.
 12. The composition according to claim 11, whereinthe noradrenergic agent is selected from the group consisting ofdiethylpropion, mazindol, phenylpropanolamine, phentermine,phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazinetartrate and combinations thereof.
 13. The composition according toclaim 11, wherein the serotonergic agent is selected from the groupconsisting of sibutramine, fenfluramine, dexfenfluramine, fluoxetine,fluvoxamine, paroxtine and combinations thereof.
 14. The compositionaccording to claim 11, wherein the thermogenic agent is selected fromthe group consisting of ephedrine, caffeine, theophylline, selectiveβ3-adrenergic agonists and combinations thereof.
 15. The compositionaccording to claim 1, wherein the at least one obesity controlmedication is administered to a mammal in an amount ranging from about 1to about 1000 milligrams of obesity medication per day.
 16. Thecomposition according to claim 1, wherein the at least one sterol or5α-stanol absorption inhibitor is administered to a mammal in an amountranging from about 0.1 to about 1000 milligrams of sterol or 5α-stanolabsorption inhibitor per day.
 17. The composition according to claim 1,wherein the at least one obesity control medication is an alpha-blockingagent.
 18. The composition according to claim 1, wherein the at leastone obesity control medication is a kainite or AMPA receptor antagonist.19. The composition according to claim 1, wherein the at least oneobesity control medication is a leptin-lipolysis stimulated receptor.20. The composition according to claim 1, wherein the at least oneobesity control medication is a phosphodiesterase enzyme inhibitor. 21.The composition according to claim 1, wherein the at least one obesitycontrol medication is a compound having nucleotide sequences of themahogany gene.
 22. The composition according to claim 1, wherein the atleast one obesity control medication is a fibroblast growth factor-10polypeptide.
 23. The composition according to claim 1, wherein the atleast one obesity control medication is a monoamine oxidase inhibitor.24. The composition according to claim 23, wherein the monoamine oxidaseinhibitor is selected from the group consisting of befloxatone,moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone,pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide,milacemide, caroxazone and combinations thereof.
 25. The compositionaccording to claim 1, wherein the at least one obesity controlmedication is a compound for increasing lipid metabolism.
 26. Thecomposition according to claim 1, wherein the at least one obesitycontrol medication is a lipase inhibitor.
 27. A pharmaceuticalcomposition for the treatment or prevention of obesity or lowering aconcentration of a sterol or 5α-stanol in plasma of a mammal, comprisinga therapeutically effective amount of the composition of claim 1 and apharmaceutically acceptable carrier.
 28. A method of treating orpreventing obesity or lowering a concentration of a sterol or 5α-stanolin plasma of a mammal, comprising the step of administering to a mammalin need of such treatment an effective amount of the composition ofclaim
 1. 29. A therapeutic combination comprising: (a) a first amount ofat least one obesity control medication, and (b) a second amount of atleast one sterol absorption inhibitor or 5α-stanol absorption inhibitor;wherein the first amount and the second amount together comprise atherapeutically effective amount for the treatment or prevention ofobesity or lowering a concentration of a sterol or 5α-stanol in plasmaof a subject.
 30. The therapeutic combination of claim 29, wherein theat least one sterol or 5α-stanol absorption inhibitor is represented byFormula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: Ar¹ and Ar² are independently selected from the groupconsisting of aryl and R⁴-substituted aryl; Ar³is aryl or R⁵-substitutedaryl; X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R and R² areindependently selected from the group consisting of—OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R¹ and R³ are independently selected from thegroup consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0or 1; m, n and p are independently selected from 0, 1, 2, 3 or 4;provided that at least one of q and r is 1, and the sum of m, n, p, qand r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1,the sum of m, q and n is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituentsindependently selected from the group consisting of lower alkyl, —OR⁶,—O(CO)R⁶, O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁷, —NR SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(loweralkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN, —NO₂ and halogen; R⁵ is 1-5substituents independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷,—NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁-₁₀CONR⁶R⁷, -(loweralkylene)COOR⁶ and —CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen, lower alkyl, aryl andaryl-substituted lower alkyl; and R⁹ is lower alkyl, aryl oraryl-substituted lower alkyl.
 31. The therapeutic combination accordingto claim 29, wherein the at least one obesity medication is administeredconcomitantly with the at least one sterol or 5α-stanol absorptioninhibitor.
 32. The therapeutic combination according to claim 29,wherein the at least one obesity medication and the at least one sterolor 5α-stanol absorption inhibitor are present in separate treatmentcompositions.
 33. A method of treating or preventing obesity or loweringa concentration of a sterol in plasma of a subject, comprising the stepof administering to a subject in need of such treatment an effectiveamount of the composition of claim
 29. 34. A method of treating orpreventing obesity comprising the step of administering to a subject inneed of such treatment an effective amount of a composition comprisingat least one sterol or 5α-stanol absorption inhibitor.
 35. A method oftreating or preventing obesity comprising the step of administering to asubject in need of such treatment an effective amount of a compositioncomprising at least one sterol absorption inhibitor represented byFormula (II) below: